Monday, March 31, 2014

Advances in the Treatment of Hepatitis C

Advances in the Treatment of Hepatitis C as seen at CROI 2014

March 28, 2014
By Mariel Selbovitz

The opening day of the 21st Conference on Rtroviruses and Opportuistic Infections (CROI 2014) featured a press conference on advances in the treatment of hepatitis C, with a focus on how new drugs may be used in the real world, given barriers such as high cost and a shortage of experienced medical providers.

As new Hepatitis C drugs are approved, more clinical trial options become available and interferon-free regimens near FDA approval, Hepatitis C treatment is changing rapidly. Several presentations at CROI 2014 focused on what has become the ever-evolving face of Hepatitis C treatment.

Anita Kohli presented data from the first three arms of the eight arm SYNERGY study1. The objective of the SYNERGY study is to use multiple drugs to target various stages of the HCV life cycle with the goal of shortening the duration of therapy.

Twenty treatment-naive patients were enrolled in each of the study arms for a total of 60 study participants. Four different drugs were used (2 as a co-formulated fixed dose tablet) to target different stages of the Hepatitis C life cycle.

Sofosbuvir is a nucleotide NS5B polymerase inhibitor and Ledipasvir is an NS5A inhibitor, both of which were used in all three arms as a fixed dose tablet. In the first arm, this regimen was given for 12 weeks. In the second arm, GS-9669, a non-nucleoside NS5B polymerase inhibitor (which works at a different site in the NS5B region than Sofosbuvir), was added. The third arm consisted of Sofosbuvir/Ledipasvir and GS-9451. GS-9451 is a protease NS3/4 inhibitor.

The study population reflected what researchers felt was an accurate representation of the HCV patient population in the U.S. and was a difficult to treat cohort. Across the three arms of the trial the average age of participants were 54- 57; 65- 80% were male, 80-95% were black, 55- 85% had Genotype 1a and 15-45% had genotype 1b. 75-90% maintained an unfavorable Il-28B genotype of CC or TT, 65- 75% had a viral load of greater than 800, 000 IU/mL and 25-40% had stage 3 or 4 liver disease.

Study results showed that 59 of the 60 patients across all 3 arms achieved SVR 12, and that 39 of the 40 patients in the two 6 week arms achieved SVR 12 after 6 weeks of therapy.

In the Sofosbuvir/Ledipasvir group all patients were virally suppressed below the level of quantification by week 4 and remained suppressed at SVR12. In the Sofosbuvir/Ledipasvir and GS-9669 group all patients were virally suppressed by week 4 and remained suppressed at end of treatment. One African American male with stage 3 liver disease, a high viral load and genotype 1a relapsed at week 4. All other patients achieved SVR12 in this arm. In the Sofosbuvir/Ledipasvir and GS-9451 arm, all patients were virally suppressed at week 4 and remained suppressed at SVR12.

Blood draws were taken over the initial 36 hours following the first medication dose on a subset of patients (n=29). Viral kinetic analysis was performed to determine if the addition of a third agent could enhance viral clearance of HCV and to develop a future model of treatment with combination regimens that could possibly shorten therapy even further.

Researchers found the 3 drug regimen of Sofosbuvir/Ledipasvir and GS-9451 led to a significantly faster decline of virus than the other 2 regimens, at day 7, day 14 and day 21.

Rapid normalization was seen of ALT and AST across all arms with 90-100% normalization by day 14.

No deaths or discontinuations occurred. All regimens were well tolerated. The highest percentages of adverse events were headache, which was seen in 25% of the Sofosbuvir/Ledipasvir group and 25% of the Sofosbuvir/Ledipasvir and GS-9669 group, and diarrhea at 5% in the Sofosbuvir/Ledipasvir group, 25% in the Sofosbuvir/Ledipasvir and GS-9669 group and 15% in the Sofosbuvir/Ledipasvir and GS-9451 group. Two grade 3 adverse events occurred but were not related to study drugs. One was site pain from a liver biopsy and the second was vertigo in a patient with a history of severe vertigo reported at baseline.

There were 11 grade 3 laboratory abnormalities in 9 patients:
In the Sofosbuvir/Ledipasvir arm there was one case each of elevated ALT, elevated AST, elevated LDL, hyperglycemia and hypoglycemia
In the Sofosbuvir/Ledipasvir and GS-9669 arm, 2 patients experienced a-symptomatic Hypophosphatemia
In the Sofosbuvir/Ledipasvir and GS-9451 one patient who had a history of anemia experienced decreased hemoglobin and three patients experienced elevated serum creatine but 2 had been elevated at baseline and the third developed renal insufficience after initiating 1600 mg/daily ibuprofen; all three returned to normal.

While most clinical trials of next-generation hepatitis C drugs are sponsored by pharmaceutical companies, the National Institutes of Allergy and Infectious Diseases (NIAID) is conducting parallel studies in underserved populations, looking for simple, well-tolerated treatments for people prone to difficulties with poor adherence and side effects. In the NIAID SYNERGY study, Anita Kohlifrom the National Institutes of Health and colleagues evaluated brief interferon- and ribavirin-free oral DAA regimens using a fixed-dose coformulation of Gilead Science’s recently approved HCV polymerase inhibitor sofosbuvir (Sovaldi, formerly GS-7977) and NS5A inhibitor ledipasvir (formerly GS-5885).

The SYNERGY studied found overall that 6 weeks of treatment with 3 Hepatitis C drugs that targeted different steps of the Hepatitis C viral life cycle was safe and efficacious, had a very high rate of viral clearance and offered a shorter course of treatment with fewer side effects then the currently available treatment.

Several new drugs and drug combinations are proving to be safe and efficacious for use in HCV patients. Trevor Hawkins of Southwest CARE Center in Sante Fe, New Mexico presented data on all-oral combination Daclatasvir, Asunaprevir and BMS-791325 for the treatment of HCV Genotype 12.

Daclatasvir (DCV) is a once- daily NS5A replication complex inhibitor that has been studied in over 5,500 patients and has been found to have a potent pan-genotypic activity in vitro. Asunaprevir (ASV) is a twice-daily, NS3 protease inhibitor that has been studied in over 2,000 patients and is active against genotypes 1,4,5, and 6 in vitro. BMS-791325 is a twice-daily, non-nucleoside NS5B polymerase inhibitor that is active against genotypes 1,3,4,5 and 6 in vitro. Various dose and drug-to-drug interactions have been seen with all three drugs.

A1443-014 is a randomized, phase IIb, 2 arm, 166 patient, open label study where patients received study drug for 12 weeks with follow-up to SVR 48. Patients were stratified by genotype 1a or 1b and whether or not they had biopsy-confirmed cirrhosis, receiving either DCV 30 mg BID +ASV 200 mg BID + BMS-791325 75 mg BID or DCV 30 mg BID+ ASV 200 mg BID+ BMS-791325 150 mg BID.

Researchers felt the study participant demographics were common for HCV clinical trials with an average 67% of the two arms being male; average age was 54, 83% were white and 16% African American. 82% had genotype 1a and 18% had genotype 1b and 38% had either FIB-3 or FIB-4 as determined by FibroSure/FibroTest. Those with FIB-4 received biopsies and an average 9% of the two arms had cirrhosis. Two/thirds were non-CC.

Study results found 92% of study participants achieved SVR. All treatment failures occurred in Genotype 1a. There were no predictors of failure other than Genotype.

In the DCV+ASV+BMS-791325 75 mg arm, 71/77 achieved SVR-12. The most frequent adverse events in this group were headache at 21.3%, diarrhea at 15%, fatigue at 15% and nausea at 12.5%. Grade 3/4 lab abnormalities included high AST in 1 patient and high glucose fasting serum in 1 patient.

In the DCV+ASV+ BMS-791325 150mg., 77/84 patients achieved SVR-12. In this arm the most frequent adverse events were headache in 27.9%, diarrhea in 15.1% and fatigue and nausea in 8.7% each. Grade 3/4 lab abnormalities included high glucose fasting serum in 1 patient and high bilirubin in 1 patient. There was 1 discontinuation due to adverse events and one patient discontinued BMS-791325 only and added peg/IFNa/RBV for 12 weeks.

Both regimens were found to be safe and effective and researchers recommend the continuation of clinical trials into Phase III trials.

Vincent LoRe from the University of Pennsylvania reported on a multi-site Veterans Administration (VA) study3, which analyzed predicting risk of end-stage liver disease (ESLD) in HIV/HCV co-infected patients for individualized HCV therapy decisions. The study evaluated the efficacy of utilizing laboratory and clinical variables to predict end-stage liver disease in HIV/HCV patients.

Researchers utilized data from the Veterans Aging Cohort Study (VACS) to identify 4,280 co-infected patients in the VA, all of who had been on HIV antiretroviral therapy for at least one year. Data was gathered of baseline predictors that included diabetes, Hepatitis B, race, obesity, a viral load greater than 400 c/mL, CD4 count below 200 cells/mm3 and a class 4 Fibrosis rating, from the initial year on therapy.

Study participants were followed for a total of 6.8 years where researchers found 8% of patients had developed ESLD as defined by hepatic liver decomposition, hepatocellular carcinoma or liver-related death.

Researchers discovered that utilizing Fibrosis 4 rating may be an effective means of means of predicting ESLD over time and could help to inform HCV treatment decisions. Additional predictors that were measured with FIB-4 were insufficient in adding greater predictability. Ongoing analysis continues for additional predictors.

Combination Oral, Hepatitis C Antiviral Therapy for 6 or 12 Weeks: Results from the SYNERGY Trial A Kohil et al. Conference on Retroviruses and Opportunistic Infection, Boston, MA , March 3-6, 2014
All-Oral Combination of Daclatasvir, Asunaprevir, and BMS-791325 for HCV Genotype 1 Infection GT Everson et al. Conference on Retroviruses and Opportunistic Infection, Boston, MA , March 3-6, 2014
Predicting Risk of ESLD in HIV/HCV Patients for Individualized HCV Therapy Decisions V Lo Re et al. Conference on Retroviruses and Opportunistic Infection, Boston, MA , March 3-6, 2014

Sofosbuvir plus a Second Antiviral for HCV Genotype 1 Infection?

Sofosbuvir plus a Second Antiviral for HCV Genotype 1 Infection?
Atif Zaman, MD, MPH reviewing Gane EJ et al. Gastroenterology 2014.

Atif Zaman, MD, MPH

Preliminary data show promising results for interferon-free regimens with ledipasvir and GS-9669, even among patients with cirrhosis and prior null response.

Atif Zaman, MD, MPH

Sofosbuvir-based regimens are currently approved for the treatment of hepatitis C virus (HCV) infection. However, the most effective sofosbuvir-based regimens for genotype 1 infection still include interferon, and few data are available regarding the efficacy in treatment-experienced patients.

To test the safety and efficacy of two interferon-free, sofosbuvir-based regimens in patients with HCV genotype 1 infection, researchers enrolled 113 patients (including 38 prior null responders and 19 with cirrhosis) to receive sofosbuvir (400 mg daily) and ledipasvir (90 mg daily) plus ribavirin (1000–1200 mg daily) for 6 weeks or 12 weeks, or sofosbuvir and GS-9669 (500 mg daily) plus ribavirin for 12 weeks. The primary endpoint was sustained virologic response (SVR) at 12 weeks posttreatment.

Results are as follows:
In treatment-naive patients, the SVR rate was 100% (25 of 25) for the 12-week regimen of sofosbuvir, ledipasvir, and ribavirin; 68% (17 of 25) for the 6-week regimen; and 92% (23 of 25) for the regimen of sofosbuvir, GS-9669, and ribavirin.

Among prior null responders without cirrhosis, the SVR rate was 100% for both regimens (a total of 19 patients).

Prior null responders with cirrhosis received sofosbuvir and ledipasvir with and without ribavirin, and respective SVR rates were 100% (9 of 9) and 70% (7 of 10).

Side effects were mild and included headache, fatigue, and nausea.

The findings of this small, early study demonstrate that interferon-free, sofosbuvir-based regimens will likely be effective in patients with HCV genotype 1 infection, even those with cirrhosis and prior null response. However, they also suggest that a very short course of therapy such as 6 weeks may be inadequate, and for the most difficult-to-treat subgroups, ribavirin will likely still be needed.

Editor Disclosures at Time of Publication

Gane EJ et al. Efficacy of nucleotide polymerase inhibitor sofosbuvir plus the NS5A inhibitor ledipasvir or the NS5B non-nucleoside inhibitor GS-9669 against HCV genotype 1 infection. Gastroenterology 2014; 146:736. (

PubMed abstract (Free) - See more

Saturday, March 29, 2014

Gilead says has discounted hepatitis C drug for some health plans

Gilead says has discounted hepatitis C drug for some health plans

By Deena Beasley
Sat Mar 29, 2014 12:13pm EDT

(Reuters) - Gilead Sciences Inc, under fire for pricing a new hepatitis C drug at $1,000 a pill, has discount agreements with a number of health insurers, a company executive said in an interview.

The medication, Sovaldi, has a list price of $84,000 for a 12-week course of therapy and is seen as a breakthrough in the treatment of the serious liver disease.

It has been shown to raise cure rates and cut treatment time with fewer side effects than older medicines, but critics maintain that a price of $1,000 each is too high for an easy-to-make pill needed by millions of Americans.

On March 20, Democratic lawmakers led by California Representative Henry Waxman asked Gilead to explain the price tag, and a meeting with the company is scheduled for next week.

Health insurers and state Medicaid programs for the poor are pushing for further discounts, fearing a multibillion-dollar pricetag from treating most hepatitis C sufferers with Sovaldi and similar new medicines likely to be approved in coming years.

Gilead shares have dropped 9 percent in the last week on concerns over the pushback on drug pricing. The news has also weighed on other biotechnology companies that are banking on their ability to command high prices for new treatments.

"It's the volume (of patients) payers are looking at here. It's not the price," said Gregg Alton, Gilead's executive vice president, corporate and medical affairs. "A lot of them are looking for a discount, but I think the real issue here is how many patients they now have in their plans that need hepatitis C treatment."

The Centers for Disease Control and Prevention estimates that about 3.2 million Americans are infected with hepatitis C, a liver-destroying virus transmitted through blood.

If each were treated with full-priced Sovaldi, the cost would be $269 billion. Gilead already provides a mandated discount off its list price to U.S. government health plans and insurers at about 23 percent.

Alton said the company has deals for "supplemental discounts" for government-funded agencies such the Veterans Administration and the Department of Defense, on top of the 23 percent. He would not provide details.

He said the VA, which accounts for about 10 to 15 percent of the hepatitis C population in the United States, has been "proactive" in recognizing the need to treat the disease, which can lead to liver failure and necessitate liver transplants.

He estimated that patients eligible for Medicaid, the government-funded health plan for the poor, account for another 10 to 15 percent of Americans with hepatitis C.

Alton singled out health maintenance organization Kaiser Permanente for taking action to secure Sovaldi, also at a discount, for its patients.

"We have an arrangement with Kaiser that works very well for both of us," the Gilead executive said. "They recognize that if they make the investment today, they get all the benefit."

He said that is because many Kaiser patients stay for many years with the organization known for quality, integrated care, even into retirement when they qualify for a managed Medicare plan. So Kaiser's upfront investment treating hepatitis C will pay off years later by averting future costs of liver disease. Kaiser officials were not immediately available for comment.

But many traditional insurers can't rely on the same kind of stability among their policyholders, who tend to switch health plans more frequently, meaning they cannot be sure of the same savings over time.

"One of the challenges we have with some insurers is that the benefits may not come to them," the Gilead executive said. "No matter how we price this product, the benefits and the savings are going to come later."

Alton also sees the concerns over a deluge of patients demanding immediate treatment as unlikely to materialize.

"Most of the patients are not diagnosed, and many aren't seeking care currently," he said. "This is going to take some time."

ISI Group analyst Mark Schoenebaum noted on Friday data showing that new prescriptions of Sovaldi had dropped 5 percent in the past week. He estimated that Gilead's 2014 U.S. sales of Sovaldi, which was approved by the Food and Drug Administration late last year, will total as much as $9 billion even if it sees no new prescription growth.

(Reporting By Deena Beasley; Editing by Michele Gershberg, Tom Brown and David Gregorio)


Friday, March 28, 2014

Shared Medical Appointments and Hepatitis C Update

Shared Medical Appointments and Hepatitis C Update - Health Matters

Health Matters
Premiere Date: 3/20/2014; 28 minutes

The way we treat medical conditions is constantly evolving. From new ways of distributing medical information to new drugs and therapies.

Alexander Kuo, MD joins David Granet, M.D., F.A.C.S., F.A.A.P. to discuss how he uses shared medical appointments to give his patients in-depth care. Dr. Kuo also highlights new treatments for hepatitis C

Study takes on fatty liver disease


Thursday, March 27, 2014

European Medicines Agency Validates Gilead’s Marketing Application for Ledipasvir/Sofosbuvir

Related Feb 10 - Gilead Files for U.S. Approval:Ledipasvir/Sofosbuvir Fixed-Dose Combo For Genotype 1 Hepatitis C

press release
March 27, 2014, 4:10 p.m. EDT

European Medicines Agency Validates Gilead’s Marketing Application for Ledipasvir/Sofosbuvir Fixed-Dose Combination Tablet for Genotype 1 Chronic Hepatitis C Infection

-- If Approved, Once-Daily Tablet Would Simplify Therapy and Eliminate Need for Interferon and Ribavirin for Genotype 1 Hepatitis C Patients in Europe ---- LDV/SOF Granted an Accelerated Assessment by the European Medicines Agency --

FOSTER CITY, Calif., Mar 27, 2014 (BUSINESS WIRE) -- Gilead Sciences, Inc. /quotes/zigman/72849/delayed/quotes/nls/gild GILD +0.27% today announced that the company’s Marketing Authorisation Application (MAA) for a once-daily fixed-dose combination of the NS5A inhibitor ledipasvir (LDV) 90 mg and the nucleotide analog polymerase inhibitor sofosbuvir (SOF) 400 mg for the treatment of chronic hepatitis C virus (HCV) genotype 1 infection, has been fully validated and is now under assessment by the European Medicines Agency (EMA). The data included in the application, which was submitted on February 27, 2014, support the use of LDV/SOF among adult patients with genotype 1 HCV infection for eight or 12 weeks, depending on prior treatment history and whether they have cirrhosis.

Genotype 1 is the most prevalent form of HCV in Europe, and accounts for 60 percent of infections worldwide. Current treatments for genotype 1 HCV include pegylated interferon and ribavirin (RBV), which may not be suitable for certain patients.

“Based on the results of the Phase 3 ION studies, LDV/SOF has the potential to transform HCV therapy for genotype 1 patients by eliminating the need for interferon injections and ribavirin and reducing the duration of treatment,” said Norbert Bischofberger, PhD, Executive Vice President of Research and Development and Chief Scientific Officer. “If approved, LDV/SOF would be the first all-oral treatment option that has the potential to cure HCV in as little as eight weeks.”

The MAA for LDV/SOF is supported by three Phase 3 studies, ION-1, ION-2 and ION-3, in which nearly 2,000 genotype 1 HCV patients were randomized to receive the fixed-dose combination, with or without RBV, for treatment durations of eight, 12 or 24 weeks. Trial participants included patients who were treatment-naïve or who had failed previous treatment, including protease inhibitor-based regimens, and patients with compensated cirrhosis.

Review of the MAA will be conducted under the centralized licensing procedure, which, when finalized, provides one marketing authorization in all 28 member states of the European Union. The EMA has accepted Gilead’s request for accelerated assessment of LDV/SOF, a designation that is granted to new medicines of major public health interest.

LDV/SOF is an investigational product and its safety and efficacy has not yet been established. Although accelerated assessment of this investigational fixed-dose combination could shorten EMA’s review time by approximately two months, it does not guarantee a positive opinion from the EMA’s Committee for Medicinal Products for Human Use (CHMP) or final approval by the European Commission. If approved, LDV/SOF could be available for marketing in the EU by the end of 2014. Gilead has also submitted regulatory applications for LDV/SOF in the United States and Canada.

SOF as a single agent was granted marketing authorization in the European Union on January 16, 2014 under the tradename Sovaldi®, and is available in the United Kingdom, Ireland, Germany, France, Austria, Sweden and Finland. Sovaldi is also approved in the United States, Canada, New Zealand and Switzerland.

About Gilead Sciences

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

Forward-Looking Statement

This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including the risk that the European Commission and other regulatory agencies, including in the United States and Canada, may not approve the LDV/SOF fixed-dose combination in the currently anticipated timelines or at all, and any marketing approvals, if granted, may have significant limitations on its use. Further, additional clinical studies of LDV/SOF, including results from the 24-week arms of ION-1, may produce unfavorable results. As a result, Gilead may not be able to successfully commercialize LDV/SOF, and may make a strategic decision to discontinue its development if, for example, the market for the product fails to materialize as expected. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. The reader is cautioned not to rely on these forward-looking statements. These and other risks are described in detail in Gilead’s Annual Report on Form 10-K for the year ended December 31, 2013, as filed with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation to update any such forward-looking statements.

EU full prescribing information for Sovaldi is available at .

Breaking The Bank: Sovaldi And The Cost-Innovation Paradox In The US Healthcare System

Breaking The Bank: Sovaldi And The Cost-Innovation Paradox In The US Healthcare System

Last week, three senior members of the House Energy and Commerce Committee caused quite a kerfuffle in the investment community by sending biotech giant Gilead Sciences a letter demanding management justify the $84,000 price tag for Sovaldi (sofosbuvir), a recently-approved treatment for chronic hepatitis C (HCV)........
By any objective metric, Sovaldi is a good value. The drug costs less on an absolute basis than Incivek (~$100,000 per year), which is reimbursed without question, and is an even better deal if one applies a “cost per cure” methodology (A recent Mt. Sinai study shows a $189,000 cost per cure for Incivek-containing regimens.) Moreover, remember that the government pays nowhere near list price; Medicaid receives a mandatory 23.1% discount on branded drug prices (Sovaldi is covered by privately-administered Medicare Part D plans for patients over 65 years old)......

Full story: Forbes

February Updates 
Reducing the cost of new hepatitis C drugs
Sovaldi Investigation Finds Revenue-Driven Pricing Strategy Behind $84,000 Hepatitis Drug
Check out an index of articles pointing the reader to the current controversy over the high price of Sovaldi, Harvoni (ledipasvir/sofosbuvir) and AbbVie Viekira Pak.

CAIRO:CPA warns of adulterated hepatitis C drugs

CPA warns of adulterated hep. C drugs

CAIRO: The Customer Protection Agency (CPA) warned Wednesday against buying adulterated drugs for hepatitis C virus (HCV) or liver disease, saying such drugs are not registered at the Ministry of Health.

The agency received complaints from patients about the HCV drug AFA-KLAMATH, which costs 1,300 to 2,100 EGP (U.S. $ 186 to 301), CPA chairperson Atef Yaqoub said in a press statement. The drug was falsely advertised on satellite channels as “a German product” and a “substance taken from a plant cell that looks like a human cell,” the Yaquob said.

In coordination with the Egyptian Drug Authority (EDA) of the Ministry of Health, the agency managed to seize nine bottles of the drug, as well as other illegal aphrodisiacs drugs and expired medicine in two pharmacies in Cairo and Giza, the statement said.

When asked if seizing the drugs came in framework of a campaign launched by the CPA, Amir Koumy, head of CPA branch in Cairo, told The Cairo Post that the agency moved after receiving patient complaints that the drug was ineffective.

Usually the CPA launches campaigns on specific products at time and is currently, for instance, conducting a campaign on plastics, Koumy added.

Around 18 million people are infected with HCV and 7.5 million have kidney failure in Egypt, according to statistics from institutes of live disease and kidney failure, Koumy noted.

WHO reports around 20 percent of Egyptian blood donors are infected with HPV, or “anti-HCV positive,” while around 150 million persons are infected worldwide.

Combating the false advertising of drugs, CPA established a year and half ago a media observer to keep an eye on advertisements in order to removed fraudulent drugs from the market, Koumy said.

Koumy said the government was planned to address the problem, and that ”there will be a meeting with the Prime Minister Ibrahim Mahlab within the coming ten days to discuss this issue,” he said.


Wednesday, March 26, 2014

Medscape Special Report: New Hepatitis C Guidance

From Medscape Gastroenterology 

Special Report: New Hepatitis C Guidance

March 26, 2014


New HCV Guidance: Rapid Updates for Clinicians
The implications of the new HCV guidance for all clinicians are discussed by Paul Martin, MD (member of the writing panel), and Helen Boucher, MD, in an interview with Medscape.

Joining Forces to Combat Hepatitis C
Drs. Paul Sax and David Thomas reflect on how the worlds of gastroenterology and infectious disease have joined to meet the need for fast-paced guidance in hepatitis C treatment.

New HCV Interim Treatment Recommendations Available
A new HCV Web site helps clinicians keep up with the rapidly changing environment in HCV treatment.

Approximately 1% of US Residents Have Chronic HCV Infection
About 2.7 million US residents in the population sampled by NHANES 2003-2010 have chronic HCV infection, which is about 500,000 fewer than a similar estimate for 1999-2002.

The HCV Revolution Did Not Happen Overnight

This article is part of the HCV Therapies special issue.

March 13, 2014
Pages 210-269
In this issue:


Evolving Therapies for the Treatment of HCV Viral Hepatitis

George Painter (Guest Editor)
CEO, DRIVE—Drug Innovation Ventures at Emory, LLC.
ACS Med. Chem. Lett., 2014, 5 (3), pp 212–213
DOI: 10.1021/ml500064y
Publication Date (Web): March 13, 2014
Copyright © 2014 American Chemical Society

Hepatitis is a general term referring to inflammation of the liver, a condition that can result from infection with a virus, bacterium, or a parasitic organism, or alternatively from noninfectious causes such as alcohol, drugs, or autoimmune disease. Viral infections are responsible for over half of all diagnosed cases of hepatitis. While a number of viruses replicate in multiple organs including the liver, hepatitis viruses are defined as those that show a primary tropism for the liver. These viruses include types A, B, C, D, E, and F (not confirmed). Of these, types A, B, and C are the most common. Infection with these viruses can lead to acute disease characterized by symptoms of nausea, abdominal pain, fatigue, malaise, and jaundice. Severe cases of acute viral hepatitis can rapidly progress to acute liver failure. Additionally, hepatitis B virus (HBV) and hepatitis C virus (HCV) infection can lead to chronic infection. Patients who are chronically infected with HBV or HCV have a high probability of developing cirrhosis and/or hepatocellular carcinoma. Chronic hepatitis carriers remain infectious and can transmit the disease for many years postinfection.

While the population impact of HBV infection has long been appreciated (it is still the leading cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma worldwide), the epidemiology of HCV infection and its significance to world health has only become clear in the last two decades.(1) HCV infection is extremely widespread and has put an enormous burden on the world healthcare system. In July of 2013, the World Health Organization (WHO) reported that HCV is found worldwide with some countries having chronic infection rates in excess of 5% of the population (Egypt, for example, has the largest known burden of HCV infection with a 10% incidence in persons aged 15 to 59).(2) Seroprevalence data suggests that as many as 185 million people are infected worldwide and consequently are at risk of developing cirrhosis and/or hepatocellular carcinoma. It is estimated that an additional 3 to 4 million people will be infected with HCV every year with 350,000 people dying from HCV related liver disease annually. The virus is most commonly transmitted through (1) receipt of contaminated blood products or organ transplants, (2) contaminated syringes and needle-stick injuries in health care settings, (3) injection drug abuse, and (4) transmission to a neonate by a hepatitis C infected mother.

Complete eradication of a pathogenic virus is the goal of antiviral therapy, but this has often proven to be difficult if not impossible to achieve. However, a sustained virologic response (SVR) to treatment for HCV infection, as measured by viremia, has been shown to significantly reduce liver-related morbidity, as well as all-cause mortality in chronically infected patients. Until 2011, the standard of care was treatment with a combination of interferon alpha given once weekly as a subcutaneous injection and ribavirin given orally twice daily for 24 to 48 weeks. Fewer than half of those infected with genotype 1 virus (there are six genotypes of virus, 1 through 6, with multiple subtypes in each genotype) were cured by this treatment regimen, and many patients were ineligible or unable to tolerate it. Clearly, additional treatment options were needed. Two direct acting antiviral agents, boceprevir and telaprevir, that selectively target the virally encoded NS3/4A protease received United States FDA regulatory approval in 2011. Both of these drugs are indicated in combination with pegylated interferon and ribavirin, and their inclusion in the treatment regimen led to higher rates of SVR. However, because of sequence variability in the NS3 protease across genotypes, these drugs are only indicated for the treatment of genotype 1. By mid-2012, additional direct acting antivirals targeting the NS3/4A protease, the NS5B polymerase, and the NS5A protein (involved in formation of the viral replicase complex) were in various stages of clinical development. In late 2013, the United States Food and FDA-granted approvals for two additional HCV drugs. Sofosbuvir, a first-in-class NS4B inhibitor, was approved in combination with pegylated interferon alpha and ribavirin for patients infected with genoytpes 1 and 4, and in combination with ribavirin alone for patients infected with genotypes 2 and 3 (use of the drug in combination with ribavirin alone is also allowed in patients infected with genotype 1 who are interferon ineligible). The NS3/4A protease inhibitor, simeprivir, also received approval for treatment of patients infected with genotype 1 virus, including patients with cirrhotic livers, in combination with pegylated alpha interferon and ribavirin. On the basis of clinical results with the approved drugs and on data emerging from additional drugs in late stage clinical trials, there is considerable optimism that an interferon alpha and ribavirin sparing combination can be identified that has pangenotypic activity and that has a high SVR, even in patients with advanced liver disease.

Despite these considerable advances in the treatment of chronic HCV infection, more research and development effort is needed. Clinical experience with the treatment of HIV, HBV, and various herpesvirus infections has shown that over time multiple drugs and drug combinations are necessary for continued control of viral replication and continued interruption of the pathogenic course of disease. These additional drugs and combination regimens were needed due to the pharmacokinetic and metabolic variability found in larger populations, as well as the impact of various coincident medical conditions on drug efficacy. Also, although the development of drug resistance and treatment breakthrough has not yet proven to be as big of an issue for HCV as it has been for other viruses, there is no guarantee that it will not become an issue as drugs are more widely used. In addition, the global burden of HCV infection is mostly found in Africa, the Middle East, and Asia where HCV genotypes 4, 5, and 6 are common. These genotypes are relatively uncommon in the West where pivotal treatment trials for the new drugs were conducted. Consequently, it is not clear if the currently approved drugs or the drugs currently under development will be effective in these populations. It is also true that the current standard of care treatments that are available in developed nations are not affordable in these regions, and more affordable medicines will be required.

As a consequence of this, the editors of ACS Medicinal Chemistry Letters thought it would be timely to put together a special issue of the journal dedicated exclusively to the current research and patents in this very important area. I was pleased to serve as the Guest Editor for this special issue.

Views expressed in this editorial are those of the author and not necessarily the views of the ACS.

Related; From HCV Therapies special issue. 


The HCV Revolution Did Not Happen Overnight

Ann D. Kwong *
InnovaTID, Inc., 125 Cambridge Park Drive, Cambridge, Massachusetts 02140, United States
ACS Med. Chem. Lett., 2014, 5 (3), pp 214–220
DOI: 10.1021/ml500070q
Publication Date (Web): February 27, 2014
Copyright © 2014 American Chemical Society
*E-mail: Phone: 617-501-3453.

The progress in HCV therapy in the last three years is similar to the progress that took HIV therapy 14 years. We are at the brink of approval for an all-oral drug combination that is dosed once daily as a single pill, has >95% efficacy, and is well tolerated. This article summarizes the path to this success and the challenges still ahead...........

Read More..........

Tuesday, March 25, 2014

Liver Damage From Opioid/Acetaminophen Combination Products

Opioid/Acetaminophen Combination Products
A few days ago CNN reported on the FDA's recommendation that physicians stop prescribing pain medication that contain more than 325mg of acetaminophen.

Acetaminophen is commonly found in over the counter medication, the most popular is Tylenol. Acetaminophen is also combined in many prescription products, usually opioids, for example codeine (Tylenol with Codeine), oxycodone (Percocet), and hydrocodone (Vicodin).

To reduce the risk of liver damage, in 2011 the FDA asked drug manufacturers to limit the amount of acetaminophen in prescription medication, which were predominantly opioid products; to no more than 325 milligrams(mg) of acetaminophen in each tablet or capsule.  The FDA also required manufacturers to update labels warning consumers of the potential risk for severe liver injury.

Although, over the counter acetaminophen products were not affected by the FDA's action, in the fall of 2011 new dosing instructions for TYLENOL were put in place by Johnson & Johnson. The maximum daily dose was changed from 8 pills (4,000 milligrams) per day to 6 pills (3,000 milligrams) per day. The drug company also changed the dosing interval from every 4-6 hours to every 6 hours.

An update from the FDA was issued this past January asking health care professionals to stop prescribing and dispensing painkillers that exceed 325 mg of acetaminophen. In the same release, the FDA reported 50% of manufacturers followed the FDA's request to lower acetaminophen, moving forward the FDA will begin proceedings to withdraw approval of any drug products that still remain on the market containing too much acetaminophen.

Many consumers are often unaware that many products (both prescription and OTC) contain acetaminophen, making it easy to accidentally take too much. In an effort to improve regulation of OTC products the FDA is holding a public hearing today and tomorrow to obtain information and comments from consumers. 

Hepatitis C And Acetaminophen
Generally experts agree low dosages of acetaminophen can safely be used in most patients with chronic hepatitis C infection. According to the Veterans Affairs website (updated July 30, 2013) the maximum recommended dose of acetaminophen (Tylenol®) for patients with hepatitis C is two grams or (four 500mg tablets) per day, but people with cirrhosis should use only one gram or two 500mg tablets per day. It goes without saying, people who actively consume alcohol should avoid taking acetaminophen altogether.

Of Interest

Cirrhosis - Warning About NSAIDS
According to this publication by the University of Michigan health System, patients with cirrhosis should avoid pain medications called “non‐steroidal anti‐inflammatories (NSAIDS)” which include over‐the‐counter medications such as ibuprofen (Motrin, Advil), naprosyn (Aleve), as well as some prescription medications.

Additional Reading

March 2014
Acetaminophen Toxicity: What Pharmacists Need to Know
Acetaminophen-induced liver toxicity has become the most common cause of acute liver failure and the second most common cause of liver failure requiring transplantation.10,11 Therefore, it is imperative that pharmacists recognize signs and symptoms of overdose and toxicity, and counsel their patients on proper dosing and usage.

Although progress has been made, some things are still to be determined. The FDA Advisory Committee has voted in favor of many changes thought to improve safety and decrease toxicity, yet the FDA has not yet taken action. For example, while the maximum daily dose of acetaminophen was previously set at 4 g/day, the FDA Advisory Committee suggests decreasing it in an effort to reduce overdoses. It is important to note that some manufacturers have already updated their labeling to reflect these recommendations, although it is not yet mandatory to do so. Efforts are also being made to improve product labeling, enhance patient education, create a universal pediatric formulation, eliminate acetaminophen combination products, and reduce the strength of OTC acetaminophen products to 325 mg per tablet with a maximum single dose of 650 mg. While no final consensus on any of these issues has been reached, healthcare providers should educate their patients on the importance of following labeling instructions.......

OTC Drug Dangers You Should Know About
Michael Lynch, MD, medical director of the Pittsburgh Poison Center at the University of Pittsburgh Medical Center, sees many patients who take OTC drugs for something other than their main intended use. “A common one I hear is people taking Tylenol PM just to sleep,” said Dr. Lynch. “But that also has acetaminophen in it; and if you’re taking too much, it can lead to toxicity.”

How to protect your liver when taking prescription and over-the-counter medications, herbal remedies or other drugs
The liver is the body's clearinghouse for most drugs, herbal remedies, vitamins and supplements which means it is vulnerable to the toxic consequences of inadvertent overdoses, unexpected interactions or extended use. View the following tips to help safeguard your liver health and ensure that the medications and remedies you need to take achieve their desired effect......

Bottom Line
The FDA reported;  most cases of severe liver injury occurred in patients who took more than the prescribed dose of an acetaminophen-containing product in a 24-hour period, took more than one acetaminophen-containing product at the same time, or drank alcohol while taking acetaminophen products. 

Make sure you take your prescription and over-the-counter (OTC) medicine properly, read the package insert or label in order to calculate your daily intake of acetaminophen.  As mentioned, remember that many narcotic combination pills and over-the-counter cold and flu medications contain acetaminophen.

For important information check out;, a website ran by the Acetaminophen Awareness Coalition, which offers information on some 600 medications that contain acetaminophen.

While you're there play the "Game of Life" and test your "Acetaminophen Knowledge." 

Stay healthy!

Monday, March 24, 2014

Reliability of stem cell 'breakthrough' questioned

The stem cell findings
could not be replicated by
other researchers
Reliability of stem cell 'breakthrough' questioned

"Stem cell 'breakthrough data inappropriately handled'," BBC News reports.

In January, scientists in Japan described how they used acid baths to simply and cheaply generate stem cells.

But the BBC has reported that this widely heralded breakthrough for stem cell science may not be all it seems.

The news follows the publication of a report into an investigation of the researchers and their work by their own academic institution, RIKEN.

The interim RIKEN report says that it appears that some of the images used in the article – which was published in the peer-reviewed journal, Nature – were actually taken from another piece of research.

There have also been allegations that some of the methodology provided in the study was "copied" from another study.

Possibly of greatest concern is that other research teams have used the techniques described in the original study (using acid baths to generate stem cells), but have failed to replicate the results as described. Analysis by independent researchers has suggested that the original research is "not reproducible".

BBC News quotes Professor Kenneth Ka-Ho Lee, of the Chinese University of Hong Kong, as saying: "The ease and simplicity of their method for generating STAP cells [the name given to stem cells produced by this method] from various stressors and cell types have left the readers in doubt.

"We have tried our very best to generate STAP cells using their protocol, and it appears that it is not as simple and reproducible as we expected. So whether the technique really works still remains an open question."

RIKEN is continuing to investigate the research and the scientists involved.

Edited by NHS Choices. Follow Behind the Headlines on Twitter. Join the Healthy Evidence forum.

Gilead scrambles toward hep C cure-all with next-gen combo pill

Gilead scrambles toward hep C cure-all with next-gen combo pill

March 24, 2014 | By

"This molecule is very important (for) Gilead longer term because the "holy grail" of hep C treatment would be a pan-genotypic one pill once per day regimen," Schoenebaum wrote in a hastily penned note to investors Monday morning....
The biotech--under intense criticism for pricing Sovaldi at $84,000 in the U.S. for the 12-week treatment--posted an abstract for the upcoming meeting of the European Association for the Study of the Liver that outlined 100% cure rates among small groups of patients across 6 genotypes taking one of two doses of a Sovaldi combination treatment. The big add here is GS-5816, a next-gen NS5A inhibitor that added the essential ingredient for a new regimen that promises to eliminate any need for interferon as well as ribavirin.

Read more
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India-Plea against Gilead's patent bid

Plea against Gilead's patent bid

MUMBAI: A patient group and a UK-based intellectual property law firm have together filed a patent opposition before the Delhi Patent Office to prevent US-based pharma company Gilead from gaining protection on a life-saving hepatitis-C drug in India. Gilead is expected to soon apply for an approval from Drug Controller General of India (DCGI) for sofosbuvir.

The move by the Delhi Network of Positive People (DNP+) and Initiative for Medicines Access and Knowledge (I-MAK) is the second pre-grant opposition filed on the drug - the first was filed last year at the Kolkata Patent Office.

Gilead Sciences has applied for multiple patents in India on sofosbuvir. India's patent law allows third parties, including civil society organizations, to file 'pre-grant' oppositions to challenge the patent application before the patent is granted. Two pre-grant oppositions by civil society groups have now been filed in India on key patents that would provide exclusivity over sofosbuvir.

The civil society groups' intention is to prevent unmerited patent applications from being granted, and to open up the market for generic producers and increase competition, which will result in lower prices and increased access.

"To get a patent under the law, you need to show that your drug is scientifically new. We believe that Gilead does not meet this lawful requirement. Opposing the patent at the examination stage is a way of ensuring patients have access to this drug at affordable prices without unnecessary patent barriers standing in the way," said Tahir Amin, director intellectual property at I-MAK.

Gilead has reportedly said that the drug will be available in India at $2,000 for a 12-week treatment.

The World Health Organization estimates that over 12 million people in India may be chronically infected by the hepatitis (HCV) virus, most of whom do not know they are infected. Treatment is improving dramatically: potent oral medications, called direct-acting antivirals (DAAs), are dramatically increasing cure rates.

New DAAs - including sofosbuvir, approved by the USFDA in December 2013, and many others in late-stage development - can be produced generically in India and marketed at very affordable prices, just like antiretrovirals (ARVs) used in the treatment of HIV.

For example, a 12-week course of sofosbuvir, produced generically, is estimated to cost between $130-270; daclatasvir, a highly effective drug from a different class, produced by BMS, may cost only $10-30 per treatment course.

Researchers take mathematical route to fighting viruses

Researchers take mathematical route to fighting viruses

Mathematicians at the University of York have joined forces with experimentalists at the University of Leeds to take an important step in discovering how viruses make new copies of themselves during an infection.

The researchers have constructed a mathematical model that provides important new insights about the molecular mechanisms behind virus assembly which helps to explain the efficiency of their operation.

The discovery opens up new possibilities for the development of anti-viral therapies and could help in the treatment of a range of diseases from HIV and Hepatitis B and C to the "winter vomiting bug" Norovirus and the Common Cold. The research is published in the Proceedings of the National Academy of Sciences (PNAS).

The researchers led by Professor Reidun Twarock, of the Departments of Mathematics and Biology at York, have established a theoretical basis for the speed and efficiency with which viruses assemble protective protein containers for their genetic information – in this case an RNA molecule - during an infection.

By incorporating multiple specific contacts between the genomic RNA and the proteins in the containers, and other details of real virus infections, the research team's mathematical model demonstrates how these contacts act collectively to reduce the complexity of virus formation, thus solving a longstanding puzzle about virus assembly – a form of Levinthal's Paradox. This also ensures efficient and selective packaging of the viral genome and has evolved because it provides significant selective advantages to viruses that operate this way.

Professor Twarock, a member of the York Centre for Complex Systems Analysis (YCCSA), said: "This truly interdisciplinary effort has provided surprising insights into a fundamental mechanism in virology. Existing experimental techniques for studying viral assembly are unable to identify the cooperative roles played by all the important components, highlighting the need and power of mathematical modelling. This model is a paradigm shift in the field of viral assembly. It sheds new light on virus assembly in a major class of viruses and their evolution, and opens up a novel strategy for antiviral therapy."

Professor Peter Stockley, of the Astbury Centre for Structural Molecular Biology at the University of Leeds, added: "These results provide a new perspective for our understanding of virus assembly, highlighting important features in the process that had previously been overlooked. We have already obtained proof of principle in a simple model virus that these functions can be targeted by drugs. The new opportunities for anti-viral intervention opened up by our paper also apply to viruses for which therapeutic options are currently limited. The new approach is enticing because it enables us to target co-operative aspects of viral assembly that are conserved across different viral strains, making it less likely that drug therapy would elicit resistance mutations. "


The research was funded by Engineering and Physical Sciences Research Council, the Biotechnology and Biological Sciences Research Council and the University of York.

EASL - Bristol-Myers to Present Data for Daclatasvir in Multiple Investigational All-oral Combinations

Bristol-Myers Squibb to Present Data for Daclatasvir in Multiple Investigational All-oral Combinations across Hepatitis C Genotypes at The International Liver CongressTM

Daclatasvir data demonstrates potential to address high unmet needs, including cirrhotic and treatment-experienced patients, and those with genotypes 1, 2, 3 and 4

Breadth of viral hepatitis data underscores Company's commitment to advancing research of liver diseases


"The wealth of data we are sharing at the International Liver Congress continue the positive momentum for daclatasvir after the Marketing Authorization Application was validated for Accelerated Regulatory Review by the European Medicines Agency, highlighting the important potential role for daclatasvir-based regimens in Europe."

PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE:BMY) announced today that 12 abstracts have been accepted for presentation at The International Liver CongressTM, the 49th annual meeting of the European Association for the Study of the Liver (EASL), in London, April 9 - 13.

Key presentations include:

Two sets of pivotal results from a global, Phase III study (HALLMARK DUAL) investigating the efficacy and safety of an all-oral, interferon- and ribavirin-free regimen of daclatasvir and asunaprevir, including data in cirrhotic and non-cirrhotic patients with HCV genotype 1b infection, will be presented as late-breakers.

Virologic response results from analyses investigating daclatasvir in combination with sofosbuvir across genotypes 1, 2 and 3.

Virologic response and safety data for the investigational all-oral 3DAA regimen (daclatasvir/asunaprevir/BMS-791325) in genotype 4 patients, as well as bioequivalence data for the daclatasvir 3DAA regimen, which is being studied as a fixed-dose-combination treatment with twice daily dosing.

"These results are encouraging and show the potential of daclatasvir across multiple treatment regimens, with the goal of helping patients achieve cure regardless of genotype, stage of disease or response to previous therapies," said Brian Daniels, MD, senior vice president, Global Development and Medical Affairs, Research and Development, Bristol-Myers Squibb.

"The wealth of data we are sharing at the International Liver Congress continue the positive momentum for daclatasvir after the Marketing Authorization Application was validated for Accelerated Regulatory Review by the European Medicines Agency, highlighting the important potential role for daclatasvir-based regimens in Europe."

Bristol-Myers Squibb is studying a broad portfolio of compounds in hopes of providing flexible treatment options to address the diverse unmet medical needs of a global HCV patient population. These investigational compounds include daclatasvir, an investigational NS5A replication complex inhibitor that has shown high antiviral potency and pan-genotypic activity across HCV genotypes in vitro; asunaprevir, an investigational NS3 protease inhibitor; BMS-791325, an investigational non-nucleoside inhibitor of the NS5B polymerase; and peginterferon lambda-1a (Lambda), an investigational type III interferon that has the potential to offer an alternative to alfa-interferon.

The complete list of Bristol-Myers Squibb data presentations is below. Abstracts can be accessed on the ILC/EASL website at
Title  Date/Time   
Hepatitis C: Direct-Acting Antiviral Data   

Oral Presentation (late-breaker) : All-oral dual therapy with daclatasvir and asunaprevir in patients with HCV genotype 1b infection: Phase 3 study results
April 12, 15:30 - 17:30   

Poster (late-breaker) : Efficacy and safety of daclatasvir in combination with asunaprevir (DCV+ASV) in cirrhotic and non-cirrhotic patients with HCV genotype 1b: Results of the HALLMARK DUAL study
April 10, 09:00 - April 12, 18:00   

Oral Presentation : Effect of baseline NS5A polymorphisms on virologic response to the all-oral combination of daclatasvir + sofosbuvir ± ribavirin in patients with chronic HCV infection
April 11, 16:00 - 18:00   

Poster : Effect of ribavirin on the safety profile of daclatasvir + sofosbuvir for patients with chronic HCV infection
April 12, 09:00 - 18:00   

Poster : All-oral therapy with daclatasvir in combination with asunaprevir and BMS-791325 for treatment-naive patients with chronic HCV genotype 4 infection
April 12, 09:00 - 18:00   

Poster : Daclatasvir, asunaprevir, and BMS-791325 in a fixed-dose combination: A phase 1 bioavailability study in healthy volunteers
April 12, 09:00 - 18:00   

Hepatitis B: Peginterferon Lambda-1a Data  

Poster : Peginterferon Lambda-1a pharmacokinetics in subjects with impaired renal function
April 12, 09:00 - 18:00   

Oral : Peginterferon Lambda for the treatment of chronic hepatitis B (CHB): A phase 2b comparison with peginterferon alfa in patients with HBeAg-positive disease
April 12, 15:30 - 17:30   

Hepatitis C: Global Health Economics and Outcomes Research (GHEOR)  

Oral Presentation : External validation of the risk-prediction model for hepatocellular carcinoma (HCC) from the REVEAL-HCV study using data from the U.S. Veterans Affairs (VA) health system
April 10, 16:00 - 18:00   

Poster : The impact of fibrosis on the risk of long-term morbidity and mortality in chronic hepatitis C patients treated in the veterans administration health care system
April 11, 09:00 - 18:00   

Poster : Early virologic responses and adverse events from the comparative assessment of effectiveness of antiviral therapies in hepatitis C study (CMPASS)
April 12, 09:00 - 18:00   

Poster : Determining the comparative effectiveness of emerging treatment regimens for hepatitis C virus (HCV) infection from single arm phase III trials
April 12, 09:00 - 18:00

About Hepatitis C
Hepatitis C is a virus that infects the liver and is transmitted through direct contact with infected blood and blood products. Up to 90 percent of those infected with hepatitis C will not spontaneously clear the virus and will become chronically infected. According to the World Health Organization, up to 20 percent of people with chronic hepatitis C will develop cirrhosis; of those, up to 25 percent may progress to liver cancer. In the European Union (EU) an estimated 9 million people are living with hepatitis C, and an estimated 170 million people worldwide are infected with the virus.

About Bristol-Myers Squibb's HCV Portfolio

Bristol-Myers Squibb's research efforts are focused on advancing late-stage compounds to deliver the most value to patients with hepatitis C. At the core of our pipeline is daclatasvir (DCV), an investigational NS5A replication complex inhibitor that has been studied in more than 5,500 patients as part of multiple direct-acting antiviral (DAA) based combination therapies. DCV has shown a low drug-drug interaction profile, supporting its potential use in multiple treatment regimens and in people with co-morbidities.

In 2014, the U.S. Food and Drug Administration (FDA) granted Bristol-Myers Squibb's investigational DCV Dual Regimen (daclatasvir and asunaprevir) Breakthrough Therapy Designation for use as a combination therapy in the treatment of genotype 1b HCV infection.

In 2013, Bristol-Myers Squibb's investigational all-oral 3DAA Regimen (daclatasvir/asunaprevir/BMS-791325) also received Breakthrough Therapy Designation, which helped to expedite the start of the ongoing Phase III UNITY Program. Study populations include non-cirrhotic naïve, cirrhotic naïve and previously treated patients. The daclatasvir 3DAA regimen is being studied as a fixed-dose-combination treatment with twice daily dosing.

Daclatasvir is also being investigated in combination with sofosbuvir in high unmet need patients, such as pre- and post-transplant patients, HIV/HCV co-infected patients, and patients with genotype 3, as part of the ongoing Phase III ALLY Program.

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

EASL-Simeprevir plus sofosbuvir with/without ribavirin data to be presented

New Simeprevir data will be presented at The International Liver Congress 2014 of the European Association for the Study of the Liver, (EASL)

Presentations Include late-breaking final results from the phase II COSMOS study

Stockholm, Sweden — Medivir AB (OMX: MVIR) today announces that new data from the clinical development program for simeprevir in the treatment of genotype 1 or genotype 4 chronic hepatitis C virus (HCV) in adult patients with compensated liver disease will be presented at The International Liver Congress of the European Association for the study of the Liver (EASL). The International Liver Congress 2014 will take place from April 9-13 in London, United Kingdom.

Eight oral and poster presentations spanning over the phase II and phase III development program for simeprevir in treatment combinations with and without ribavirin and interferon are planned. New analyses of data from the phase III QUEST-1, QUEST-2 and PROMISE clinical trials of simeprevir in combination with pegylated interferon and ribavirin, as well as final data from the phase II COSMOS study will be presented during the Congress.

The data to be presented at the International Liver Congress 2014 include:

Late-Breaking Presentations
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)
- Lead Author: Eric Lawitz; The Texas Liver Institute, University of Texas Health Science Center, San Antonio, USA

Once-daily simeprevir (TMC435) with peginterferon/ribavirin in treatment-naïve or treatment-experienced chronic HCV genotype-4 infected patients: SVR12 results of a Phase 3 trial (RESTORE Study)
- Lead Author: Christopher Moreno; ULB Hôpital Erasme, Brussels, Belgium

Oral Presentations
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 Cohort 1 subgroup analysis
- Lead Author: Mark Sulkowski; Johns Hopkins University School of Medicine, Baltimore, USA

Simeprevir with peginterferon/ribavirin for treatment of chronic HCV genotype 1 infection in European patients who relapsed after previous interferon-based therapy: the PROMISE trial
- Lead Author: Xavier Forns; Liver Unit, Hospital Clinic, Barcelona, Spain

Poster Presentations
Simeprevir (TMC435) with peginterferon/ribavirin for treatment of chronic HCV genotype 1 infection in treatment-naïve European patients in the QUEST-1 and QUEST-2 Phase 3 trials
- Lead Author: Graham R. Foster; Queen Mary’s, University of London, London, UK

Simeprevir reduces time with peginterferon/ribavirin-induced symptoms and quality-of-life impairments: 72-week results from three Phase 3 studies
- Lead Author: Jane Scott; Janssen

Virology analyses of simeprevir in Phase 2b and 3 studies
- Lead Author: Oliver Lenz; Janssen

Deep sequencing analyses of minority baseline polymorphisms and persistence of emerging mutations in HCV genotype 1-infected patients treated with simeprevir
- Lead Author: Bart Fevery; Janssen

Full session details and data presentation listings for The International Liver Congress 2014 can be found at

Medscape Video - Hepatitis C: A Disease That Straddles 2 Worlds

Watch Medscape Video - Here

Hepatitis C: A Disease That Straddles 2 Worlds

Paul E. Sax, MD: Hi. This is Dr. Paul Sax from Brigham and Women's Hospital and Harvard Medical School. Today we have a very special guest, Dr. David Thomas, Chief of Infectious Diseases and Professor of Medicine at Johns Hopkins University. Our topic will be hepatitis C virus (HCV) infection.

Dave, why don't we start by talking about the new guidelines[1] that were issued at the beginning of 2014. Why the new guidelines? What are the key messages, and what can we expect going forward?

David L. Thomas, MD, MPH: That's a great question, Paul. The reason for new guidelines is that we anticipate a season in HCV when there will be a string of new developments, in particular the approval of new antiviral therapies for HCV infection. The pace of drug development made the old process -- developing guidelines over a year and a half and having various stages of approval by every vested entity, followed by the publication of those guidelines in a peer-reviewed journal -- very impractical and not likely to be helpful, and it guaranteed that they would always be months, if not years, out of date.

That inevitability led a number of individuals from the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) to partner with the International Antiviral Society to develop guidance that would be available right when you need it, yet enabling the guidance to be updated using the Web so that it would be current -- which is really the way that medicine is practiced nowadays anyway.

Dr. Sax: It's an interesting collaboration and it brings up something that I have always found very interesting about HCV, which is that it straddles 2 worlds, sometimes more in one world than the other. Those are the worlds of the gastroenterologists and the infectious disease specialists. How did the process go for the 2 groups together?

Dr. Thomas: Historically, the AASLD has provided the most authoritative guidelines for HCV management. That was logical, because even before the virus was discovered, it was known to be a liver disease primarily because individuals would have persistently elevated liver enzyme levels and eventually would develop cirrhosis. So, historically, the liver societies have embraced the condition, and after the discovery of the virus, that didn't change substantially. But all along, some infectious disease specialists were interested in HCV, of course, because it is a viral infection and they wanted to participate in the care of patients. So it was inevitable that there would be a partnership like this.

It actually went amazingly well. The AASLD recognized that, because of our experience with HIV, the IDSA (and infectious disease specialists in general) had some experience with rapid development of new therapies and the use of online guidelines, such as what we use for antiretroviral agents. So it was a natural partnership for a society that historically had the authoritative information on HCV to partner with another society with a vested interest that also had experience with rapid updates for antiviral therapies.

Dr. Sax: That makes a lot of sense. One thing that you have probably noticed, because you have been interested in HCV for a long time (but many infectious disease doctors are coming to relatively recently), is that the infectious disease clinicians, especially those who manage HIV, take to this very readily for the reasons that you describe.

Dr. Thomas: It has been very interesting. There has been a rapid -- especially in the last year -- uptick in interest in treating HCV. It's expanding quickly, especially among HIV providers. That's logical. Previously there was a bit of an impasse on the use of interferon. Infectious disease specialists often weren't trained in using interferon and felt uncomfortable with it, and also questioned to some extent the risk-benefit ratio for the patients. But that has changed with the use of direct-acting antiviral agents with which we are extremely comfortable and experienced.
Recommending a Not-Yet Approved Regimen

Dr. Sax: If I could put you on the spot: What aspect of the guidelines would you say -- and I mean you personally, because I know you can't speak on behalf of the guidelines -- was the riskiest and most important recommendation that you made?

Dr. Thomas: The most interesting aspect of the guidance that was initially put on the Website at the end of January is the recommendation to use simeprevir and sofosbuvir for the treatment of genotype 1 hepatitis C infection in persons who are intolerant to interferon. The reason that I mention that particular recommendation is that these 2 drugs were not approved by the US Food and Drug Administration (FDA) to be used together. However, each drug has had substantial preclinical and clinical testing to be used with interferon and ribavirin. We had presented (but not published) data[2] in 167 patients on the efficacy of that combination with or without ribavirin. So that brought an interesting element into the recommendations -- in particular, what we would do with the fact that the FDA hadn't yet had a chance to fully consider phase 3 data for this combination. But we had extremely compelling data that had been presented publicly, on 167 patients treated with this combination, and in one of the most difficult-to-treat and important patient groups. So I found that one to be very interesting.

Dr. Sax: Yes, I would completely agree. When the 2 drugs were approved, I was able to poll some readership of the Massachusetts Medical Society blog that I write and ask what readers thought was the recommended treatment for genotype 1 patients. Most chose that exact combination. So, clearly we are heading toward an interferon-free future, and we are already there, so this is a very difficult question to answer. (That's why I get to ask the questions and you are Chief of Infectious Diseases at Johns Hopkins.) What would you say is the next wave of drugs, and how are they going to be used? You don't have to state agents specifically, but feel free to just talk about trends.

Dr. Thomas: There are additional regimens that have completed phase 3 testing and are under consideration by the FDA. We are anticipating that we will have interferon-sparing regimens for genotype 1 HCV that are fully vetted and approved for that indication. Those should be available in 6 months or so, so that is easy to answer and quite exciting. Right now, we already have FDA-approved, interferon-sparing treatments for genotype 2 and genotype 3 HCV infection, but with most patients in the United States having genotype 1 (and especially in some locations such as Baltimore, where more than 85% of HCV is genotype 1), there is substantial interest in a fully vetted FDA-approved genotype 1 interferon-sparing regimen. That is exciting in the near term.

Dr. Sax: l will mention some of the drugs that are currently being considered. One is a 3-active agent, but 4- or 5-drug regimens are being developed by AbbVie. You are familiar with those. Give me a sense of where you see them fitting in.

Dr. Thomas: That regimen and the medications that Gilead has developed -- a coformulation of 2 medications -- are exciting developments for treatment of genotype 1 infection. On the basis of what we have seen published and presented on those medications, I estimate that they will become very important parts of our formulary and our approach to genotype 1 HCV infection as soon as this fall.
HCV Guidance: An Intentional Work in Progress

Dr. Sax: That's very exciting. Are there any particular parts of the guidelines that you think deserve to be mentioned, perhaps about special populations or the treatment of patients who have previously failed treatment or had no response?

Dr. Thomas: The guidelines are a work in progress, and that is intended. In the initial phase there is guidance on the initial treatment of patients with all HCV genotypes. There is also information on re-treatment for patients with all genotypes. There is information on some special populations, including, for example, HIV-coinfected patients, patients with renal disease, and patients with cirrhosis. It is not so much a cookbook as a strong recommendation to refer patients with more advanced disease to liver specialists for transplantation evaluation. That's the kind of information in the guidance. In addition, there is information on testing, screening, and linkage to care.

What is coming will be information on whom and when to treat. Right now the guidance that is available says that if you are going to treat, this is what you should use to treat the patient. It doesn't actually say which patients should be treated right now and how we would sort that out. That information, which is very important, should be forthcoming in about 3 months. In addition, there should be some new information on the management of patients with acute HCV infection and the critical question of what is the best way to monitor someone while they are on treatment and after treatment. So that is what's coming and what is there already.
HCV News From CROI 2014

Dr. Sax: It is a very dynamic area of both research and clinical practice -- the two of them going in parallel. It's really quite exciting. We just had the Conference on Retroviruses and Opportunistic Infections (CROI) up here in Boston, and I apologize on behalf of our city for the weather that we threw at you. What did you think were the most interesting stories in basic science research or clinical research from CROI related to HCV?

Dr. Thomas: There were many very interesting HCV presentations at CROI. There was additional information on several different interferon sparing-regimens both in patients with HIV and those without HIV. That is exciting, and it was exciting to see the incremental progress in the field. One that stands out was the presentation of the so-called SYNERGY trial.[3] That study was done at the National Institutes of Health, where they tested the hypothesis that therapy could be abbreviated to 6 weeks in patients who were given very potent medications right from the beginning. They were given a nonstructural 5A (NS5A)-acting medication along with a nucleotide inhibitor in all instances, and then patients in 2 arms were given either a protease inhibitor along with that or a nonnucleoside protease inhibitor -- another way of inhibiting the polymerase. The hypothesis was that by acting in multiple steps in the viral life cycle, and doing that quickly, we might be able to abbreviate therapy. There are 20 patients in those 2 arms and then another 20 patients who received what you might consider the standard of care, which was the NS5A drug ledipasvir, along with the nucleotide inhibitor sofosbuvir.

Dr. Sax: It's funny that you would say that's the standard of care.

Dr. Thomas: Yes. It's funny because it's not FDA-approved and it's probably a misuse of the word "standard of care," but it's the gold standard because that medication has gone all the way through phase 3 testing, and we have a real strong sense of what would happen with the use of that medication for 8-12 weeks. That is the control population. What happened was that either 19 or 20 out of the 20 patients had sustained virologic responses in those 6-week arms.

That was very interesting in the sense that we are starting to push the envelope on just how short therapy can be and still be effective -- something that we didn't know beforehand. A year and a half ago, I don't think anyone who was honest would have predicted that we could abbreviate therapy that much and still have a very low relapse rate.

It really brings up a basic science question, which is, why is that? What is it about the RNA template -- the source of new viruses -- that we thought would be stable in a hepatocyte and endure there? Therefore, if you don't kill the cell and that RNA template is allowed to persist, it would form the basis for relapse, which we see even with 6 and 12 months of suppressed viral replication in other contexts. So that information is very interesting, and it starts to shake up our understanding not just of how we approach treatment but also what is going on inside of those cells with this RNA virus.

Dr. Sax: That is very exciting. I thought the coexistence of that study on the same program with some interferon-based regimens was like the most evolved humans and dinosaurs roaming the Earth at the same time. It really did strike a very big contrast.

Dr. Thomas: That's a great metaphor.

Dr. Sax: Is there anything else you want to say before we finish with what we can expect in the future?

Dr. Thomas: The focus of this interview was the Internet-based guidance, which you can find at I would just encourage providers to consider that as a source of information when they have questions about HCV treatment, especially if they are not able to keep up on everything or they are not a really active provider. That is a good place to go to make sure that your treatment is up-to-date and as current as it could possibly be.

Dr. Sax: Thanks very much for your time today. It was very interesting talking with you. Perhaps we will revisit this in 6 months or so and see where things have gone.


AbbVie to Present Detailed Results from Phase III Studies in Patients with Chronic Hepatitis C at the 2014 International Liver Congress™

Mar 24, 2014

NORTH CHICAGO, Ill., March 24, 2014 /PRNewswire/ -- AbbVie (NYSE: ABBV) will present new data from its phase III hepatitis C development program at the 2014 International Liver Congress™ (ILC) in London, April 9-13. Detailed results from the SAPPHIRE-I, SAPPHIRE-II, PEARL-III, and TURQUOISE-II studies will be presented at the ILC on April 10-12.

In presentations at the ILC, investigators will share detailed data results of four studies from AbbVie's phase III clinical trial program, the largest phase III program of an investigational, all-oral, interferon-free regimen for the treatment of chronic hepatitis C virus (HCV) infection in genotype 1 (GT1) adult patients.

Following is a list of AbbVie's phase III clinical trial program data being presented at the ILC:
SAPPHIRE-II: Phase III Placebo-Controlled Study of an Investigational Interferon-Free, 12-Week Regimen in 394 Treatment-Experienced Adults with HCV GT1
Oral Presentation: General Session 1 and Opening
April 10, 14:00-14:15 BST; ICC Auditorium
SAPPHIRE-I: Phase III Placebo-Controlled Study of an Investigational Interferon-Free, 12-Week Regimen in 631 Treatment-Naive Adults with HCV GT1
Oral Presentation: General Session 2 and Awards 1
April 11, 10:15-10:30 BST; ICC Auditorium
PEARL-III: Sustained Virologic Response 12 Weeks Post-treatment (SVR12) with an Investigational 12-Week Regimen in 419 Treatment-Naive HCV GT1b-Infected Adults
Late Breaker Poster: Poster P1299
April 12, 9:00-18:00 BST; Poster Exhibition
TURQUOISE-II: SVR12 Rates in 380 HCV GT1-Infected Adults with Compensated Cirrhosis Treated with an Investigational Regimen
Oral Presentation: Late Breakers
April 12, 15:30-15:45 BST; ICC Auditorium

AbbVie will present additional data in presentations throughout the Congress. The full ILC 2014 scientific program can be found at

About AbbVie's Investigational HCV Regimen
The AbbVie investigational regimen consists of the fixed-dose combination of ABT-450/ritonavir (150/100mg) co-formulated with ABT-267 (25mg), dosed once daily, and ABT-333 (250mg) with or without ribavirin (RBV) (weight-based), dosed twice daily. The combination of three different mechanisms of action interrupts the HCV replication process with the goal of optimizing sustained virologic response (SVR) rates across different patient populations.

Additional information about AbbVie's phase III studies can be found on

AbbVie's HCV Development Program
The AbbVie HCV clinical development program is intended to advance scientific knowledge and clinical care by investigating an interferon-free, all-oral regimen with and without RBV with the goal of producing high SVR rates in as many patients as possible, including those that typically do not respond well to treatment, such as previous non-responders to interferon-based therapy or patients with advanced liver fibrosis or cirrhosis.

ABT-450 was discovered during the ongoing collaboration between AbbVie and Enanta Pharmaceuticals (NASDAQ: ENTA) for HCV protease inhibitors and regimens that include protease inhibitors. ABT-450 is being developed by AbbVie for use in combination with AbbVie's other investigational medicines for the treatment of HCV.

Safety Information for Ribavirin and Ritonavir
Ribavirin and ritonavir are not approved for the investigational use discussed above, and no conclusions can or should be drawn regarding the safety or efficacy of these products for this use.

There are special safety considerations when prescribing these drugs in approved populations.

Ritonavir must not be used with certain medications due to significant drug-drug interactions and in patients with known hypersensitivity to ritonavir or any of its excipients.

Ribavirin monotherapy is not effective for the treatment of chronic hepatitis C virus and must not be used alone for this use. Ribavirin causes significant teratogenic effects and must not be used in women who are pregnant or breast-feeding and in men whose female partners are pregnant. Ribavirin must not be used in patients with a history of severe pre-existing cardiac disease, severe hepatic dysfunction or decompensated cirrhosis of the liver, autoimmune hepatitis, hemoglobinopathies, or in combination with peginterferon alfa-2a in HIV/HCV co-infected patients with cirrhosis and Child-Pugh score ³6.

See approved product labels for more information.

About AbbVie
AbbVie is a global, research-based biopharmaceutical company formed in 2013 following separation from Abbott Laboratories. The company's mission is to use its expertise, dedicated people and unique approach to innovation to develop and market advanced therapies that address some of the world's most complex and serious diseases. AbbVie employs approximately 25,000 people worldwide and markets medicines in more than 170 countries. For further information on the company and its people, portfolio and commitments, please visit Follow @abbvie on Twitter or view careers on our Facebook or LinkedIn page.

Forward-Looking Statements
Some statements in this news release may be forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995. The words "believe," "expect," "anticipate," "project" and similar expressions, among others, generally identify forward-looking statements. AbbVie cautions that these forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those indicated in the forward-looking statements. Such risks and uncertainties include, but are not limited to, challenges to intellectual property, competition from other products, difficulties inherent in the research and development process, adverse litigation or government action, and changes to laws and regulations applicable to our industry.

Additional information about the economic, competitive, governmental, technological and other factors that may affect AbbVie's operations is set forth in Item 1A, "Risk Factors," in AbbVie's 2013 Annual Report on Form 10-K, which has been filed with the Securities and Exchange Commission.

AbbVie undertakes no obligation to release publicly any revisions to forward-looking statements as a result of subsequent events or developments, except as required by law.


For further information: Media: Elizabeth Hoff, +1 (847) 935-4236,; Javier Boix, +1 (847) 937-6113,; Investor Relations: Elizabeth Shea, +1 (847) 935-2211,