HHS Dr Koh releases update to National Viral Hepatitis Action Plan & highlights 10 big advances propelling progress

Provided by The Huffington Post

Updated Viral Hepatitis Action Plan Released

Dr. Howard K. Koh
Assistant Secretary for Health, U.S. Department of Health and Human Services

Posted: 04/02/2014 4:18 pm EDT Updated: 04/03/2014 9:59 am EDT

Today we are pleased to release an updated version of the nation's first comprehensive cross-governmental action plan to combat chronic viral hepatitis, initially launched in 2011. The Action Plan for the Prevention, Care and Treatment of Viral Hepatitis (2014-2016) builds upon the substantial progress accomplished over the past three years by agencies and offices across the Department of Health and Human Services - as well as within the Departments of Justice and Veterans Affairs. (Read a brief factsheet about the updated plan.)

Chronic viral hepatitis (hepatitis B [HBV] and hepatitis C [HCV]) is a largely preventable and treatable disease. Yet it affects between 3.5 and 5.3 million Americans, most of them unaware of their infection. As a result, untreated chronic viral hepatitis represents the leading cause of liver cancer and the most common reason for liver transplantation in the United States. In addition, it is a leading infectious cause of death in the U.S., claiming the lives of 12,000-18,000 Americans each year.

But we are making progress against this "silent epidemic." The release of the first Action Plan has galvanized progress on many fronts. Here are just 10 of the recent accomplishments in the field:

1. Establishment of National Hepatitis Testing Day. The original Action Plan called for the establishment of this annual observance, which we've now observed on May 19th each year since 2012. National Hepatitis Testing Day raises greater awareness among both health care providers and communities and we look forward to another outstanding observance next month.

2. New hepatitis C testing recommendations. Both the CDC and the U.S. Preventive Services Task Force have issued recommendations to test all individuals born between 1945 and 1965. As these so-called "Baby Boomers" are five times more likely to be infected with hepatitis C, this single recommendation could save over 120,000 lives. The alignment of these CDC and USPSTF recommendations and their widespread dissemination were called for in the 2011 Action Plan.

3. Expanded, culturally appropriate hepatitis B outreach and educational materials. Produced by CDC in partnership with community organizations, the Know Hep B campaign materials, available in several Asian languages, enable health care providers and community organizations to reach more individuals at risk about the importance of testing for HBV.

4. Greater attention to hepatitis C among persons who inject drugs (PWID). Of new cases of HCV infection reported to the CDC, injection drug use represents the most commonly identified risk factor. An estimated 64 percent of PWID are chronically infected with HCV, and 2.7-11 percent are chronically infected with HBV. Recent consultations and research funding announcements are strengthening our understanding of this problem. We are identifying better ways to prevent new infections in this vulnerable population.

5. Opposing discrimination against health care professionals and students with chronic hepatitis. In a great example of the cross-agency collaboration fostered by the Action Plan, the Offices of Civil Rights from the Departments of Justice, Education, and Health and Human Services sent a joint letter last year to health professions schools. The letter highlighted new CDC guidance on the management of health care professionals and students with chronic HBV and outlined steps to eliminate discrimination against those infected.

6. Greater attention to the elimination of perinatal hepatitis B transmission. We have the tools to further reduce the number of infants perinatally infected with HBV. Motivated and active partners have engaged to ensure the administration of a dose of HBV vaccine to all newborns before discharge from hospitals or birthing centers.

7. New hepatitis C treatments. Late last year, the FDA approved two new HCV treatments, which are simpler to use, require a shorter treatment duration, and have fewer side effects than earlier treatment regimens. These treatments lead to a cure in more than 90 percent of patients who complete them - a major advance. Our FDA colleagues are working along with the pharmaceutical industry to make new HCV therapies available safely and as quickly as possible by using the Fast Track program. This special designation facilitates development and review of drugs with the potential to address unmet medical needs in those with serious conditions.

8. Affordable Care Act. The Affordable Care Act is contributing to efforts to combat chronic viral hepatitis in the U.S. For example, because the law prohibits most plans from denying health coverage based on preexisting conditions, those with chronic viral hepatitis who had previously been uninsured will now have the opportunity to get covered and obtain access to needed prevention, care and treatment services. Moreover, hepatitis vaccinations and testing for HBV for pregnant women are among the covered preventive services that must be offered free of cost-sharing or co-pays. Later this year, one-time HCV screening for persons born between 1945 and 1965 will be added to this list. In addition, the law calls for a substantial investment in the HHS community health center program, which is a vital partner in delivering viral hepatitis prevention, diagnosis, care and treatment to vulnerable populations.

9. World Hepatitis Day proclamations from the President. President Obama has lent his support to the global observance of World Hepatitis Day for the past three years, issuing annual proclamations. The White House has also hosted events to commemorate these observances, helping to raise awareness and mobilize action to address viral hepatitis not only in the U.S. but around the globe.

10. An updated Action Plan for the Prevention, Care, & Treatment of Viral Hepatitis. Now, the updated Action Plan will build upon all the important advances noted above, and identify further opportunities for public and private sector stakeholders. So many can engage in efforts to break the silence surrounding viral hepatitis and improve prevention, diagnosis, care and treatment.

New partners have joined in launching the updated Action Plan. We are pleased that from the federal government, the Department of Housing and Urban Development and the White House Office of National Drug Control Policy have joined our efforts along with the HHS Office of Disease Prevention and Health Promotion, Office of Population Affairs, and our Regional Health Administrators. Many others can join as well. As my colleague Dr. Ronald Valdiserri, Deputy Assistant Secretary for Health, Infectious Diseases observes, "Active involvement by a broad mix of partners from various sectors, both public and private, is essential to fully realizing the potential of this plan. The updated plan provides a framework around which all of us can engage in aligned and focused action."

I hope you, too, will join us in this important moment. It is a critical time. We have the potential to save many lives. The era of health care reform provides a historic setting to strengthen the rapid progress we're making in the diagnosis and treatment of chronic hepatitis. Working together, we can successfully leverage all of our resources to help the nation become fully committed to combating the silent epidemic of viral hepatitis.

Share your ideas about how you or your organization can contribute to this national effort in the comments section below or on social media using the hashtag #ViralHepAction.

Follow Dr. Howard K. Koh on Twitter: www.twitter.com/@HHS_DrKoh

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Also See: Updated Action Plan to Combat Viral Hepatitis Released

The next frontier in 3-D printing: Human organs

By Brandon Griggs, CNN
updated 9:43 AM EDT, Thu April 3, 2014

(CNN) -- The emerging process of 3-D printing, which uses computer-created digital models to create real-world objects, has produced everything from toys to jewelry to food.

Soon, however, 3-D printers may be spitting out something far more complex, and controversial: human organs.

For years now, medical researchers have been reproducing human cells in laboratories by hand to create blood vessels, urine tubes, skin tissue and other living body parts. But engineering full organs, with their complicated cell structures, is much more difficult.

Enter 3-D printers, which because of their precise process can reproduce the vascular systems required to make organs viable. Scientists are already using the machines to print tiny strips of organ tissue. And while printing whole human organs for surgical transplants is still years away, the technology is rapidly developing.

"The mechanical process isn't all that complicated. The tricky part is the materials, which are biological in nature," said Mike Titsch, editor-in-chief of 3D Printer World, which covers the industry. "It isn't like 3-D printing plastic or metal. Plastic doesn't die if you leave it sitting on an open-air shelf at room temperature for too long."

Lawrence Bonassar, a professor of biomedical engineering at Cornell University, with an artificial ear made via 3-D printing and injectable molds.

The idea of printing a human kidney or liver in a lab may seem incomprehensible, even creepy. But to many scientists in the field, bioprinting holds great promise. Authentic printed organs could be used for drug or vaccine testing, freeing researchers from less accurate methods such as tests on animals or on synthetic models.

Then there's the hope that 3-D printers could someday produce much-needed organs for transplants. Americans are living longer, and as we get deeper into old age our organs are failing more. Some 18 people die in the United States each day waiting in vain for transplants because of a shortage of donated organs -- a problem that Anthony Atala, director of the Wake Forest Institute for Regenerative Medicine and a pioneer in bioprinting, calls "a major health crisis."

An 'exciting new area of medicine'

Bioprinting works like this: Scientists harvest human cells from biopsies or stem cells, then allow them to multiply in a petri dish. The resulting mixture, a sort of biological ink, is fed into a 3-D printer, which is programmed to arrange different cell types, along with other materials, into a precise three-dimensional shape. Doctors hope that when placed in the body, these 3-D-printed cells will integrate with existing tissues.

The process already is seeing some success. Last year a 2-year-old girl in Illinois, born without a trachea, received a windpipe built with her own stem cells. The U.S. government has funded a university-led "body on a chip" project that prints tissue samples that mimic the functions of the heart, liver, lungs and other organs. The samples are placed on a microchip and connected with a blood substitute to keep the cells alive, allowing doctors to test specific treatments and monitor their effectiveness.

"This is an exciting new area of medicine. It has the potential for being a very important breakthrough," said Dr. Jorge Rakela, a gastroenterologist at the Mayo Clinic in Phoenix and a member of the American Liver Foundation's medical advisory committee.

One of Organovo's engineers oversees the construction of a vascular tissue construct on a Novotel bioprinter.

"Three-D printing allows you to be closer to what is happening in real life, where you have multiple layers of cells," he said. With current 2-D models, "if you grow more than one or two layers, the cells at the bottom suffocate from lack of oxygen."

To accelerate the development of bioprinted organs, a Virginia foundation that supports regenerative medicine research announced in December it will award a $1 million prize for the first organization to print a fully functioning liver.

One early contender for the prize is Organovo, a California start-up that has been a leader in bioprinting human body parts for commercial purposes. Using cells from donated tissue or stem cells, Organovo is developing what it hopes will be authentic models of human organs, primarily livers, for drug testing.

The company has printed strips of human liver tissue in its labs, although they are still very small: four by four by one millimeter, or about one-fourth the size of a dime. Each strip takes about 45 minutes to print, and it takes another two days for the cells to grow and mature, said Organovo CEO Keith Murphy. The models can then survive for about 40 days.

Organovo has also built models of human kidneys, bone, cartilage, muscle, blood vessels and lung tissue, he said.

"Basically what it allows you to do is build tissue the way you assemble something with Legos," Murphy said. "So you can put the right cells in the right places. You can't just pour them into a mold."

Ethical concerns

Not everyone is comfortable with this bold new future of lab-built body parts, however.

A research director at Gartner Inc., the information-technology research and advisory firm, believes 3-D bioprinting is advancing so quickly that it will spark a major ethical debate by 2016.

A 3-D printer at Cornell University produces an artificial ear.

"Three-D bioprinting facilities with the ability to print human organs and tissue will advance far faster than general understanding and acceptance of the ramifications of this technology," Pete Basiliere said in a recent report.

"These initiatives are well-intentioned, but raise a number of questions that remain unanswered," Basiliere added. "What happens when complex 'enhanced' organs involving nonhuman cells are made? Who will control the ability to produce them? Who will ensure the quality of the resulting organs?"

Bioprinted organs are also likely to be expensive, which could put them out of reach of all but the wealthiest patients.

Murphy said Organovo only uses human cells in creating tissues, and doesn't see any ethical problems with what his company is doing.

"People used to worry about doing research on cadavers ... and that dissipated very quickly," he said. "We don't think there's any controversy if you're producing good data and helping people with health conditions."

Most experts, including Wake Forest's Atala, don't think we'll see complex 3-D-printed organs, suitable for transplants, for years if not decades. Instead, they believe the next step will be printing strips of tissue, or patches, that could be used to repair livers and other damaged organs.

Organovo also uses the Nuveen MMX Bio printer, which is small enough to fit into a cabinet.

"We are very eager to put pieces of tissue to work for surgical transplants," said Organovo's Murphy, who hopes his company will be ready to begin clinical trials within five years.

Of course, any use of 3-D-printed tissue in surgical procedures would require approval by the U.S. Food and Drug Administration. That review process could take up to a decade.

By then, the notion of a surgeon putting a 3-D-printed kidney into a patient may not seem so bizarre. Then again, this swiftly evolving technology may create new moral conundrums.

"The ethical questions are bound to be the same concerns we have seen in the past. Many major medical breakthroughs have suffered moral resistance, from organ transplants to stem cells," said Titsch of 3D Printer World.

"Will only the rich be able to afford it? Are we playing God? In the end, saving lives tends to trump all objections."

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Updated Action Plan to Combat Viral Hepatitis Released

FOR IMMEDIATE RELEASE
April 3, 2014

Contact: HHS Press Office
(202) 205-0143

A statement by Deputy Assistant Secretary for Health, Infectious Diseases,
Ronald O. Valdiserri, MD, MPH

Today, federal partners launched an updated Action Plan for the Prevention, Care and Treatment of Viral Hepatitis (2014-2016), building upon the nation’s first comprehensive cross-agency action plan to combat viral hepatitis.

The three-year renewal of the Action Plan builds upon the substantial progress accomplished since 2011 by agencies and offices from across the Department of Health and Human Services, as well as with our partners at the Departments of Justice, Housing and Urban Development, and Veterans Affairs, to prevent new infections and improve the diagnosis, care and treatment of individuals living with chronic hepatitis C in the United States.

Between 3.5 and 5.3 million Americans are living with chronic viral hepatitis, and most of them do not know that they are infected. Viral hepatitis is the leading cause of liver cancer and the most common reason for liver transplantation in the United States. In addition, it is a leading infectious cause of death in the U.S., claiming the lives of 12,000–18,000 Americans each year.

In recent years we have made significant progress in addressing these challenges.  With the new advances in hepatitis C treatment, more widespread availability of safe and effective vaccines for hepatitis A and B, and more opportunities for testing for hepatitis C under the Affordable Care Act, we have arrived at a critical moment. By harnessing these and other developments, we have the potential to reduce the toll of viral hepatitis in the U.S. and save many lives.

Thanks to the outstanding commitment of our public and private partners, we are closer than ever to realizing the potential of this plan.

To access the full Action Plan for the Prevention Care and Treatment of Viral Hepatitis (2014-2016) visit www.aids.gov/hepatitis.

For more information on viral hepatitis, see http://www.cdc.gov/hepatitis/.

Follow the conversation on social media using #ViralHepAction.

###

Note: All HHS press releases, fact sheets and other news materials are available at http://www.hhs.gov/news.

Like HHS on Facebook , follow HHS on Twitter @HHSgov , and sign up for HHS Email Updates.

Follow HHS Secretary Kathleen Sebelius on Twitter @Sebelius .

Last revised: April 3, 2014

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Also See: Updated Action Plan to Combat Viral Hepatitis Released

FDA approves new hand-held auto-injector to reverse opioid overdose

FDA NEWS RELEASE

For Immediate Release: April 3, 2014
Media Inquiries: Sandy Walsh, 301-796-4669, sandy.walsh@fda.hhs.gov
Consumer Inquiries: 888-INFO-FDA

First naloxone treatment specifically designed to be given by family members or caregivers

The U.S. Food and Drug Administration today approved a prescription treatment that can be used by family members or caregivers to treat a person known or suspected to have had an opioid overdose. Evzio (naloxone hydrochloride injection) rapidly delivers a single dose of the drug naloxone via a hand-held auto-injector that can be carried in a pocket or stored in a medicine cabinet.

It is intended for the emergency treatment of known or suspected opioid overdose, characterized by decreased breathing or heart rates, or loss of consciousness.

Drug overdose deaths, driven largely by prescription drug overdose deaths, are now the leading cause of injury death in the United States – surpassing motor vehicle crashes. In 2013, the Centers for Disease Control and Prevention reported the number of drug overdose deaths had steadily increased for more than a decade.

Naloxone is a medication that rapidly reverses the effects of opioid overdose and is the standard treatment for overdose. However, existing naloxone drugs require administration via syringe and are most commonly used by trained medical personnel in emergency departments and ambulances.

“Overdose and death resulting from misuse and abuse of both prescription and illicit opioids has become a major public health concern in the United States,” said Bob Rappaport, M.D., director of the Division of Anesthesia, Analgesia, and Addiction Products in the FDA’s Center for Drug Evaluation and Research. “Evzio is the first combination drug-device product designed to deliver a dose of naloxone for administration outside of a health care setting. Making this product available could save lives by facilitating earlier use of the drug in emergency situations.”

Evzio is injected into the muscle (intramuscular) or under the skin (subcutaneous). Once turned on, the device provides verbal instruction to the user describing how to deliver the medication, similar to automated defibrillators. Family members or caregivers should become familiar with all instructions for use before administering to known or suspected persons to have had an opioid overdose. Family members or caregivers should also become familiar with the steps for using Evzio and practice with the trainer device, which is included along with the delivery device, before it is needed. 

Because naloxone may not work as long as opioids, repeat doses may be needed. Evzio is not a substitute for immediate medical care, and the person administering Evzio should seek further, immediate medical attention on the patient’s behalf.

In one pharmacokinetic study of 30 patients, a single Evzio injection provided equivalent naloxone compared to a single dose of naloxone injection using a standard syringe. The use of Evzio in patients who are opioid dependent may result in severe opioid withdrawal. Abrupt reversal of opioid depression may result in nausea, vomiting, sweating, accelerated heart rate (tachycardia), increased blood pressure, uncontrollable trembling (tremulousness), seizures and cardiac arrest.

The FDA reviewed Evzio under the agency’s priority review program, which provides for an expedited review of drugs that appear to provide safe and effective therapy when no satisfactory alternative therapy exists, or offer significant improvement compared to marketed products. The product was granted a fast-track designation, a process designed to facilitate the development, and expedite the review of drugs to treat serious conditions and fill an unmet medical need.

Evzio is being approved ahead of the product’s prescription drug user fee goal date of June 20, 2014, the date the agency was originally scheduled to complete review of the drug application.

Evzio’s approval is also the result of efforts by several federal agencies. Naloxone has been a part of the White House’s Office of National Drug Control Policy’s National Drug Control Strategy since 2012. The FDA co-chairs an HHS inter-departmental working group on naloxone, which helped coordinate an April 12, 2012, meeting regarding access to naloxone products.

Evzio is manufactured for kaléo, Inc., of Richmond, Va. 
For more information:

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Exclusive: Costs to public of $84,000 hep C drug ‘outrageous' - Kaiser

By Deena Beasley
LOS ANGELES  Wed Apr 2, 2014 3:41pm EDT

(Reuters) - Kaiser Permanente, the biggest U.S. health maintenance organization, said it is using Gilead Sciences' new hepatitis C drug, Sovaldi, even though its $84,000 treatment price is "outrageous."

The medication is widely viewed as a breakthrough that can cure a majority of hepatitis C patients, often within 12 weeks. Analysts project 2017 sales of $9.1 billion, according to Thomson Reuters Pharma.

But Gilead has come under fire, from insurers and Congress, for Sovaldi's $1,000-a-pill price at a time when U.S. healthcare spending is under scrutiny and President Barack Obama's Affordable Care Act aims to make health coverage accessible to everyone.

The company says Sovaldi should create huge savings for the healthcare system over time by preventing complications from liver disease and transplants, but declined requests for evidence to back up those claims. A Gilead executive told Reuters last week that it had an agreement to discount the drug for the Kaiser network, based on their recognition of the long-term benefits.

In an interview, Kaiser officials disputed that view. Kaiser is using Sovaldi "not because we see this as a high-value, cost-effective approach," said Dr. Sharon Levine, associate director of the Permanente Medical Group. "It's because this is a therapy that represents a substantial improvement over existing therapies ... It's an outrageous price for a therapy that has huge public health implications."

She called Kaiser's discount on Sovaldi "modest" and said state Medicaid programs and private health insurers "are going to have to make very serious tradeoffs just based on a single manufacturer's decision on pricing a drug because they can."

Gilead officials declined to comment.

Hepatitis C, estimated to infect about 3.2 million Americans, is a blood-borne virus that can cause severe liver damage.

LAWMAKERS SEEK PRICING INFORMATION

Democratic lawmakers in the House of Representatives, led by California's Henry Waxman, have asked Gilead to explain Sovaldi's pricing. The company said it met with committee staff on Monday.

The public call to Gilead from Congress has sent shock waves through the biotech investment community, raising concerns that other leading drugmakers could face pressure on pricing new medicines. Over the past month the Nasdaq Biotechnology Index has fallen more than 8 percent.

Insurers and state officials running the Medicaid health program for the poor fear a multibillion-dollar tab from Sovaldi alone.

Investment bank Leerink Partners estimates the drug's cost could trim as much as 10 percent from the earnings of publicly traded health insurers.

Kaiser, a nonprofit, said Sovaldi will be a material portion of its drug budget - a cost ultimately born by members and employers who pay insurance premiums.

"It comes back to the question of who benefits at a time when there is enormous pressure to ensure that the cost of healthcare, the cost of providing access to cures doesn't bankrupt all of the rest of the investments that the country needs to make," Levine said.

(Reporting by Deena Beasley; Editing by Michele Gershberg and Prudence Crowther)

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Gilead Announces Results From Phase 3 Study of Sofosbuvir Among Hepatitis C Patients in Japan

– Results Confirm Efficacy and Safety of All-Oral Sofosbuvir-Based Regimen for Genotype 2 HCV Patients –

– Japanese Regulatory Filing Planned for Mid-Year –

FOSTER CITY, Calif.--(BUSINESS WIRE)--Apr. 2, 2014-- Gilead Sciences, Inc. (Nasdaq:GILD) today announced topline results from a Phase 3 clinical trial (Study GS-US-334-0118) in Japan evaluating the once-daily nucleotide analog polymerase inhibitor sofosbuvir in combination with ribavirin (RBV) for the treatment of genotype 2 chronic hepatitis C virus (HCV) infection. The study met its primary efficacy endpoint of superiority compared to a predefined historical control sustained virologic response (SVR) rate. In the study, 97 percent (n=148/153) of genotype 2 HCV-infected patients receiving 12 weeks of an all-oral regimen of sofosbuvir plus RBV achieved a sustained virologic response 12 weeks after completing therapy (SVR12). SVR12 rates among treatment-naïve and treatment-experienced patients were 98 percent (n=88/90) and 95 percent (n=60/63), respectively. Of the 153 patients who received treatment, 11 percent (n=17) had documented cirrhosis.

Japan has one of the highest rates of liver cancer of any industrialized country, and the majority of cases are due to chronic HCV infection. An estimated two million people in Japan are living with HCV infection, and approximately 20-30 percent have the genotype 2 strain of the virus. Current treatment options for genotype 2 HCV infection in Japan involve up to 48 weeks of therapy with pegylated interferon injections, which may not be suitable for certain patients.

In Study GS-US-334-0118, 153 patients (100%) became HCV undetectable by treatment Week 4 and remained undetectable through the remainder of the 12-week treatment period. Post-treatment relapse accounted for five virologic failures. There were no treatment discontinuations due to adverse events and all patients completed the 12 week post-treatment follow-up visit. The most common side effects observed in the study, consistent with the population and safety profile of RBV, included nasopharyngitis, anemia, headache, malaise and pruritis. Full study results will be presented at a future scientific meeting.

“This study confirms the high efficacy of all-oral therapy with sofosbuvir among genotype 2 hepatitis C patients in Japan, regardless of whether they are treatment experienced or new to treatment,” said Norbert Bischofberger, PhD, Executive Vice President of Research and Development and Chief Scientific Officer, Gilead Sciences. “Based on these trial results, Gilead anticipates submitting a New Drug Application for sofosbuvir to the Japanese Pharmaceutical and Medical Devices Agency (PMDA) by mid-2014.”

Gilead established operations in Japan with the formation of Gilead K.K. in Tokyo in September 2013. If approved by the PMDA, sofosbuvir would be the first product to be launched and marketed by Gilead in Japan.

Gilead is also conducting a Phase 3 study in Japan evaluating the efficacy and safety of a once-daily fixed-dose combination of the NS5A inhibitor ledipasvir 90 mg and sofosbuvir 400 mg with and without ribavirin for the treatment of patients with genotype 1 chronic HCV infection, the most common strain of HCV in Japan. SVR12 results are expected in the second half of 2014.

Sofosbuvir is an investigational product in Japan and its safety and efficacy has not yet been established. The compound has been approved by regulatory authorities in the United States, European Union and Canada and is commercialized under the tradename Sovaldi^®. The ledipasvir/sofosbuvir fixed-dose combination is an investigational product and its safety and efficacy has not yet been established.

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 possibility of unfavorable results from additional clinical trials involving sofosbuvir or the ledipasvir/sofosbuvir fixed-dose combination in Japan, and the possibility we may not file for regulatory approval of sofosbuvir in Japan in the currently anticipated timelines. Further, the PMDA may not approve these products in Japan, and any marketing approvals, if granted, may have significant limitations on its use. 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.

U.S. full prescribing information for Sovaldi is available at www.Gilead.com

Sovaldi is a registered trademark of Gilead Sciences, Inc.

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

Source: Gilead Sciences, Inc.

Gilead Sciences, Inc.
Patrick O’Brien, Investors, 650-522-1936
Cara Miller, Media (U.S.), 650-522-1616

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Hepatitis C Drug Trials to Take Spotlight at Liver Congress

Miriam E. Tucker
April 02, 2014

New all-oral interferon-free treatment regimens for hepatitis C will take center stage at the European Association for the Study of the Liver (EASL) International Liver Congress 2014, with an unprecedented number of phase 3 trials demonstrating cure rates of up to 100%.

The congress will take place April 9 to 13 in London, United Kingdom.

"There are a lot of very important things being discussed, but I think what really stands out are the remarkable results achieved in several trials on the treatment of hepatitis C, particularly genotype 1, which is the most difficult to treat," explained Giorgina Mieli-Vergani, MD, who is honorary president of the EASL.

"Hepatitis C is a major killer in the world, and doctors have been trying for a long time to find the best way of treating it. Now we are very close to being able to treat it very effectively — this is a major, major thing coming out of this congress," Dr. Mieli-Vergani told Medscape Medical News.

In fact, "we've never had this many phase 3 studies in one conference before, said Markus Peck-Radosavljevic, MD, secretary-general of the EASL. "They will be changing clinical practice."

Dr. Markus Peck-Radosavljevic

The studies will show that "without interferon, by combining 2 or 3 drugs, you can cure hepatitis C in 95% and 99% of cases, which means essentially you can cure everybody with very little side effect," said Dr. Peck-Radosavljevic told Medscape Medical News.

Moving "Very, Very Fast"

Some of the most highly anticipated phase 3 results are from the SAPPHIRE trials, which evaluated 12-week regimens of ribavirin plus ABT-450/r, ABT-267, and ABT-333, under development by AbbVie, in patients with genotype 1 hepatitis C. SAPPHIRE I involves treatment-naïve patients and SAPPHIRE II involves treatment-experienced patients.

Also anticipated are results from the ION-2 study, which evaluated the fixed-dose combination of sofosbuvir plus ledipasvir (Gilead Sciences), with and without ribavirin, in treatment-naïve and treatment-experienced patients with genotype 1 hepatitis C.

Dr. Giorgina Mieli-Vergani

The once-daily sofosbuvir/ledipasvir pill appears to work in a short period of time in the most difficult-to-treat patients, and with far fewer adverse effects than regimens containing pegylated interferon. Dr. Mieli-Vergani called the results "amazing."

"I am a pediatrician, and this is exceedingly exciting for me," she told Medscape Medical News. "The current oral drug regimens require up to 12 pills a day, which is impossible for a child. There are no trials in children yet, but they will follow." Although hepatitis C is much less common in children than in adults, 6% to 7% of infected mothers pass along the infection to their infants, she explained.

New treatment guidelines for hepatitis C from the World Health Organization — primarily addressing the developing world — will be presented at the meeting.

Also presented will be EASL guidelines on hepatitis C. Although they were published online in December 2013, they are already outdated, Dr. Peck-Radosavljevic told Medscape Medical News (J Hepatol. 2014;60:392-420).

"Things are moving very, very fast. We will definitely need to update again within a year," he said. The organization will probably stop printing the guidelines on paper and only house them online so that they can be continually updated, he said.

Hallway Conversation

Not officially on the agenda but sure to be discussed is the high cost of new drugs for hepatitis C. "How all people who need it are going to be able to have it, I don't know," said Dr. Mieli-Vergani.

Dr. Peck-Radosavljevic pointed out that "companies have to recover their cost of development and satisfy their investors." But, he added, "you have a drug curing a deadly disease in 100% of patients. If you put that into perspective, the pricing is not outrageous."

Both he and Dr. Mieli-Vergani predict that the prices will eventually drop, as was the case with the HIV drugs.

Beyond Hepatitis C

Beyond hepatitis C, new information on numerous liver disease-related topics, including hepatitis B and D, nonalcoholic fatty liver disease, hepatocellular carcinogenesis, liver regeneration, and noninvasive assessment of liver disease, will be featured, and beginner and advanced sonography workshops will be offered.

Of note, phase 3 data will be presented on the use of obeticholic acid (Intercept Pharmaceuticals) for the treatment of primary biliary cirrhosis.

"This is a new type of drug. It's very interesting because it's the first time in many years we will have a new drug that works in primary biliary cirrhosis," said Dr. Peck-Radosavljevic.

The current treatment, ursodeoxycholic acid, has been on the market for about 40 years. "It helps, but doesn't work for all patients, so it is really quite important to have something new here," he said.

Primary biliary cirrhosis is an autoimmune liver disease of major interest to Dr. Mieli-Vergani. She is looking forward to meeting with 40 to 50 fellow members of an international ad hoc autoimmune hepatitis interest group that meets every year at the EASL and major liver meetings, she told Medscape Medical News.

"Autoimmune liver disease is a small part of the meeting, but a very intense and important part," she said.

Another "small but important" topic is children with liver disease. They are by and large surviving into adulthood now and transitioning to adult hepatology care, Dr. Mieli-Vergani explained.

"When I started doing pediatric hepatology 40 years ago, 60% of my patients died within 2 years of diagnosis. There were many conditions we didn't understand or know how to treat. Transplantation didn't exist. Nowadays, it's about 5%," she reported.

It is challenging for adult hepatologists, she said, because these patients are very different from those who develop liver disease in adulthood. In the United Kingdom, efforts have been made to ease the transition by having pediatric, adolescent, and adult specialists coordinate care for the patient during a transition period.

"Pediatrics is a very small part of the meeting, but the fact that they have me as the honorary president is a very nice sign," she told Medscape Medical News.

Dr. Mieli-Vergani reports receiving research funding from Roche, and being a consultant for Roche, Bristol Myers Squibb, and Novartis. Dr. Peck-Radosavljevic reports consulting for or receiving speaker honoraria from BMS, AbbVie, Gilead, Merck, Roche, Lilly, Bayer, Boehringer, and GlaxoSmithKline.

Source

Two phase III trials evaluating once-daily Simeprevir and Sofosbuvir in hepatitis C infected patients have been initiated

Stockholm, Sweden — Medivir AB (OMX: MVIR) today announces that two phase III trials are recruiting patients to examine the efficacy and safety of the NS3/4A protease inhibitor simeprevir in combination with the nucleotide inhibitor sofosbuvir for the treatment of chronic genotype 1 hepatitis C virus (HCV) infection in treatment-naïve and treatment-experienced patients with and without cirrhosis.

“Positive safety and efficacy results have previously been demonstrated in genotype 1 HCV infected patients with the interferon- and ribavirin free combination of simeprevir and sofosbuvir in the phase II COSMOS study. The OPTIMIST trials aim to further consolidate these data and to explore a shorter treatment duration of eight weeks to potentially further simplify this promising treatment option,” says Charlotte Edenius, EVP Development, Medivir AB

Study design
OPTIMIST-1
The first trial, called OPTIMIST-1 or TMC435HPC3017, is a phase III, open-label, randomized study investigating the efficacy and safety of simeprevir 150 mg in combination with sofosbuvir 400 mg.
The combination will be administered once daily for 8 or 12 weeks in chronic HCV genotype 1 infected patients without cirrhosis who are HCV treatment naïve or treatment experienced. This study will enroll approximately 300 patients in the U.S. and Canada.

OPTIMIST-2
The second trial, called OPTIMIST-2 or TMC435HPC3018, is a phase III, open-label, single-arm study investigating the efficacy and safety of simeprevir 150 mg in combination with sofosbuvir 400 mg.
The combination will be administered once daily for 12 weeks in HCV genotype 1 infected patients with cirrhosis who are HCV treatment naïve or treatment experienced. This study will enroll approximately 100 patients in the U.S. and Canada.

Ribavirin will not be administered in the OPTIMIST trials. The primary efficacy endpoint in each study is the proportion of patients achieving sustained virologic response 12 weeks after the end of treatment (SVR12).

For additional information, including inclusion and exclusion criteria for these trials, please visit www.clinicaltrials.gov

COSMOS study
The combination of simeprevir and sofosbuvir was previously evaluated in the phase II COSMOS trial.
The final cohort 1 study results (SVR12) in patients without fibrosis or cirrhosis (METAVIR score of F0-2) and the interim cohort 2 study results (SVR4) in patients with fibrosis or cirrhosis (METAVIR score of F3-4) from the COSMOS study were presented at the American Association for the Study of Liver Diseases (AASLD) Annual Meeting 2013 in Washington, D.C.

Final cohort 2 results (SVR12) have been accepted for presentation at the European Association for the Study of the Liver (EASL) International Liver Congress 2014 on April 12.

For more information please contact:
Rein Piir, EVP Corporate Affairs & IR, mobile: +46 708 537 292

Medivir is required under the Securities Markets Act to make the information in this press release public. The information was submitted for publication at 13.00 CET on 2 April 2014.

About Simeprevir
Simeprevir is an NS3/4A protease inhibitor jointly developed by Janssen R&D Ireland and Medivir AB and indicated for the treatment chronic hepatitis C infection in combination with pegylated interferon and ribavirin in HCV genotype 1 and 4 infected patients with compensated liver disease, including cirrhosis.

Janssen is responsible for the global clinical development of simeprevir and has exclusive, worldwide marketing rights, except in the Nordic countries. Medivir AB will retain marketing rights for simeprevir in these countries under the marketing authorization held by Janssen-Cilag International NV. The treatment was approved for the treatment of genotype 1 hepatitis C in September 2013 in Japan and in November 2013 in Canada and the U.S. and in March 2014 in Russia. The Committee for Medicinal Products for Human Use (CHMP) recently recommended Marketing Authorisation in the European Union for the use of Simeprevir in combination with other medicinal products for the treatment of chronic hepatitis C (CHC) in adult patients. An approval is expected during Q2-2014.

About Medivir
Medivir is an emerging research-based pharmaceutical company focused on infectious diseases. Medivir has world class expertise in polymerase and protease drug targets and drug development which has resulted in a strong infectious disease R&D portfolio. The Company’s key pipeline asset is simeprevir, a novel protease inhibitor for the treatment of hepatitis C that is being developed in collaboration with Janssen R&D Ireland. The company is also working with research and development in other areas, such as bone disorders and neuropathic pain. Medivir has also a broad product portfolio with prescription pharmaceuticals in the Nordics.

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Screening for liver cancer in patients with cirrhosis

Provided by MedicalXpress

April 1, 2014

In a systematic review and meta-analysis of 47 studies with 15,158 patients, Amit Singal (University of Texas Southwestern Medical Center) and colleagues found that patients with cirrhosis who underwent surveillance (via liver ultrasound with or without measurement of serum alpha fetoprotein) for hepatocellular carcinoma (HCC) had cancers detected at an earlier stage, were more likely to receive curative instead of palliative treatment, and had longer survival. Across all the studies, the pooled 3-year survival rate was 50.8% among the 4735 patients who underwent HCC surveillance, compared to 27.9% among the 6115 patients without prior surveillance (p<0.001).

The finding of longer survival persisted after the authors limited their review to studies that took into account lead time bias. Lead time bias, as it applies to this study, is the time between when a disease would normally be diagnosed without screening and when the disease is diagnosed with screening. Detecting disease earlier through screening can sometimes appear to increase survival when instead it only prolongs the time the person has the diagnosis. However, in this case, studies that accounted for lead time bias statistically still found that screening increased survival. Among the 6 studies that adjusted for lead time bias, those who underwent HCC surveillance had 3-year survival rates of 39.7%, vs. 29.1% among those who did not (p<0.001).

The authors note that while screening for HCC in patients with hepatitis B virus (HBV) infection is supported by a large randomized trial, no such randomized trials exist for patients with cirrhosis. Therefore the authors systematically reviewed published research that evaluated whether screening was associated with improved patient outcomes. While guidelines of the American Association for the Study of Liver Diseases and European Association for the Study of the Liver recommend surveillance with ultrasound every 6 months in high-risk patients (which includes those with chronic HBV infection and/or cirrhosis), the authors note that studies have shown that surveillance in the US is performed in less than 20% of these patients nationally, with lower rates among primary care physicians than gastroenterologists/hepatologists (physicians who specialize in caring for patients with liver disease).

A limitation of the study is that the studies were quite heterogeneous, suggesting benefits of surveillance may not be uniform among all patients, and studies did not include functional status, an important factor in determining appropriate treatment.

The authors conclude, "the preponderance of data that consistently demonstrate benefits should provide sufficient rationale to recommend HCC surveillance, even in the absence of a randomized controlled trial among patients with cirrhosis."

More information: Singal AG, Pillai A, Tiro J (2014) Early Detection, Curative Treatment, and Survival Rates for Hepatocellular Carcinoma Surveillance in Patients with Cirrhosis: A Meta-analysis. PLoS Med 11(4): e1001624. DOI: 10.1371/journal.pmed.1001624

Provided by Public Library of Science

Source

Low sodium levels pre-transplant does not affect liver transplant recipient survival

PUBLIC RELEASE DATE: 1-Apr-2014 Contact: Dawn Peters
sciencenewsroom@wiley.com
781-388-8408
Wiley

Researchers report that low levels of sodium, known as hyponatremia, prior to transplantation does not increase the risk of death following liver transplant. Full findings are published in Liver Transplantation, a journal of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.

Medical evidence shows that low sodium concentration is common in patients with end stage liver disease (ESLD), with roughly half of those with cirrhosis having sodium levels below the normal range of 135-145 mmol/L. Moreover, previous research suggests that hyponatremia is linked to complications including bacterial infections, kidney failure and encephalopathy, and increases mortality in patients with ESLD. Following liver transplantation sodium levels will return to normal.

"There is much debate within the transplant community about whether to incorporate measures of serum sodium in the organ allocation system in the U.S.," explains lead author Dr. W. Ray Kim from Stanford University in Calif., and formerly with the Mayo Clinic where the research took place. "Understanding the impact of sodium concentrations in patients prior to and following liver transplantation is an important contribution to this debate."

Using data from the Organ Procurement and Transplantation Network (OPTN) researchers identified 19,537 patients 18 years of age or older who received a liver transplant in the U.S. between 2003 and 2010. Subjects were split into three groups: those with hyponatremia (sodium levels less than 130 mEq/L); normal sodium levels (serum sodium between131-145mEq/L); and hypernatremia (high sodium levels great than 145mEq/L).

"While our findings confirm that low sodium levels prior to transplant were a strong risk factor for waitlist mortality it was not associated with higher death risk following liver transplantation," concludes Dr. Kim. "Our data suggests that using serum sodium levels to determine organ allocation priority will not impact survival following a liver transplant."

###

This study is published in Liver Transplantation. Media wishing to receive a PDF of the article may contact sciencenewsroom@wiley.com

Full citation: "The Effect of Pretransplant Serum Sodium Concentration on Outcome Following Liver Transplantation." Michael D. Leise, Byung Cheol Yun, Joseph J. Larson, Joanne T. Benson, Ju DongYang, Terry M. Therneau, Charles B. Rosen, Julie K. Heimbach, Scott W. Biggins and W. Ray Kim.Liver Transplantation; (DOI: 10.1002/lt.23860).

URL: http://doi.wiley.com/10.1022/lt.23860

About the Journal

Liver Transplantation is published by Wiley on behalf of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. Since the first application of liver transplantation in a clinical situation was reported more than twenty years ago, there has been a great deal of growth in this field and more is anticipated. As an official publication of the AASLD and the ILTS, Liver Transplantation delivers current, peer-reviewed articles on surgical techniques, clinical investigations and drug research — the information necessary to keep abreast of this evolving specialty. For more information, please visit http://wileyonlinelibrary.com/journal/lt.

About Wiley

Wiley is a global provider of content-enabled solutions that improve outcomes in research, education, and professional practice. Our core businesses produce scientific, technical, medical, and scholarly journals, reference works, books, database services, and advertising; professional books, subscription products, certification and training services and online applications; and education content and services including integrated online teaching and learning resources for undergraduate and graduate students and lifelong learners.

Founded in 1807, John Wiley & Sons, Inc. (NYSE: JWa, JWb), has been a valued source of information and understanding for more than 200 years, helping people around the world meet their needs and fulfill their aspirations. Wiley and its acquired companies have published the works of more than 450 Nobel laureates in all categories: Literature, Economics, Physiology or Medicine, Physics, Chemistry, and Peace. Wiley's global headquarters are located in Hoboken, New Jersey, with operations in the U.S., Europe, Asia, Canada, and Australia. The Company's website can be accessed at http://www.wiley.com.

Source

Recent FDA approval of sofosbuvir and simeprevir. Implications for current HCV treatment

Clinical Liver Disease Volume 3, Issue 3 March 2014 Pages 65–68

M. Valerie Lin M.D., Raymond Chung M.D.

First published: March 2014 Full publication history

DOI: 10.1002/cld.332

Citing literature

From the Gastrointestinal Unit, Liver Center and Gastroenterology Division, Massachusetts General Hospital, Boston, MA.

Potential conflict of interest: Nothing to report.

Raymond T. Chung, Gastrointestinal Unit, Massachusetts General Hospital, 55 Fruit Street, Blake 4, Boston, MA 02114. E-mail: rtchung@partners.org.

Abstract

Watch a video presentation of this article

Answer questions and earn CME

Direct-Acting Antiviral Agents

NS3/NS4A Protease Inhibitors

NS3/NS4A protease inhibitors block the hepatitis C virus (HCV) NS3/NS4A protease enzymatic cleavage of the HCV C-terminal polyprotein into discrete nonstructural proteins. Telaprevir and boceprevir represent the first wave of HCV protease inhibitors. The second wave (simeprevir, ABT-450, asunaprevir) have improved pharmacokinetics and allow once-daily dosing with more tolerable side effects. Each of these agents has similar genotype and subtype coverage (less efficacious against 1a than 1b because of a lower barrier to selection for resistance) and resistance profiles. The true second-generation protease inhibitors (MK-5172) are in earlier stages of development and likely provide close to pan-genotypic antiviral activity and a higher genetic barrier to resistance.

NS5A Inhibitors

NS5A inhibitors block viral production at two steps: the HCV replication complex and the virion assembly stage. Representative drugs in development include daclastavir, ledipasvir, ABT-267, and MK-8742.

Nucleos(t)ide NS5B Polymerase Inhibitors

Nucleos(t)ide NS5B polymerase inhibitors inhibit HCV RNA-dependent RNA-polymerase activity by binding to the active site and causing early chain termination. These agents (sofosbuvir) have broad potency and a very high barrier to resistance. Because of the critical function of the highly conserved active site, mutations in this site result in crippled replication fitness. This barrier to resistance stands in stark contrast to the nonnucleoside NS5B inhibitors, which bind to the enzyme outside the active site (allosteric inhibitors) and induce conformational changes that limit access of nucleotides to the growing viral RNA.

Figure 1 shows the HCV genome, which is a small, positive-sense, single-stranded RNA virus with a 9.6-kb genome. The virus circulates as a highly lipidated molecule that closely resembles host lipoproteins. Once inside the cell, the viral genome is exposed and translated into a polypeptide of about 3000 amino acids. This polypeptide is cleaved by a combination of host and viral proteases into 10 viral proteins. These include 3 structural proteins (C, E1, E2) and 7 non-structural proteins (p7, NS2, NS3, NS4A, NS4B, NS5A and NS5B).[1]

Figure 1. Open in figure viewer   Download Powerpoint slide

The HCV RNA genome (upper line) is translated into a single long polyprotein (middle line), which is cleaved by host and viral proteases into 10 mature peptides (lower line). From reference 1.

Host Targeting Agents

Cyclophilin Inhibitors

Cyclophilin inhibitors inhibit cyclophilin A and disrupt its interaction with NS5A and the HCV replication complex, which results in impaired replication.

MicroRNA Antagonists

MicroRNA antagonists exert inhibitory effect on HCV replication by blocking a key microRNA essential for HCV RNA replication.

Sofosbuvir

Mechanism of Action

Sofosbuvir is a nucleotide analog inhibitor of HCV NS5B polymerase, targeting the HCV NS5B polymerase active site and becoming incorporated into the growing viral RNA, causing early chain termination.[2] It exerts potent antiviral activity against HCV genotypes 1 through 6.

Approved Indications

The US Food and Drug Administration (FDA) approved the use of sofosbuvir in patients with HCV genotype 1 to 4 infections. It is also approved for use in human immunodeficiency virus (HIV)/HCV coinfection and patients with hepatocellular carcinoma awaiting liver transplantation who are within Milan criteria and have a Model for End-Stage Liver Disease (MELD) score of <15.

In HCV genotype 1 treatment-naïve patients, the combination of sofosbuvir, pegylated interferon (PEG-IFN) and ribavirin (RBV) for 12 weeks yielded a sustained virologic response (SVR) of 89%; in those with multiple unfavorable baseline factors, the SVR was 71%.[3] Patients with genotype 2 who were treated with sofosbuvir and RBV for 12 weeks had a SVR of 95%-97% in treatment-naïve patients and 82%-90% in treatment-experienced patients. In patients with genotype 3, an extended duration of 24 weeks with sofosbuvir and RBV produced a SVR rate of 93% in treatment-naïve populations and 77% in treatment-experienced populations.[3-5]

The PHOTON-1 study, in which HCV/HIV-1-coinfected patients were treated with sofosbuvir and RBV for 12-24 weeks, yielded a SVR of 76% in genotype 1, 88% in genotype 2, and 92% in genotype 3 with a good safety profile and minimal drug interaction with highly active anti-retroviral therapy (HAART).[6]

Table 1 summarizes the approved uses of sofosbuvir.

Table 1. Recommended Sofosbuvir Regimens

HCV	Medications	Duration
Sofosbuvir is given orally at 400 mg daily with or without food. PEG-IFN is given at 180 μg subcutaneously once per week. RBV is given orally, is weight-based (<75 kg = 1000 mg and >75 kg = 1200 mg), and is given in two divided doses daily with food. Patients with renal impairment require an RBV dose reduction.
Genotypes 1 and 4	Sofosbuvir + PEG-IFN/RBV	12 weeks
Genotype 2	Sofosbuvir + RBV	12 weeks
Genotype 3	Sofosbuvir + RBV	24 weeks
Hepatocellular carcinoma awaiting liver transplantation	Sofosbuvir + RBV	Up to 48 weeks (or until time of liver transplantation)

Use Outside the Approved Indications

Patients with HCV genotype 1 who are ineligible for or intolerant of PEG-IFN-based regimens should consider 1) sofosbuvir and simeprevir for 12 weeks, particularly in patients with compensated cirrhosis, or 2) sofosbuvir and ribavirin for 24 weeks.

Patients with mild to moderate renal impairment and/or anemia should consider sofosbuvir and simeprevir for 12 weeks.

Patients who failed first-generation protease inhibitors and who are therefore not candidates for simeprevir-based therapy and require immediate treatment should consider sofosbuvir and PEG-IFN/RBV therapy for 12 weeks.

Patients with posttransplantation-recurrent HCV infection may be considered for sofosbuvir and simpeprevir for 12 weeks in genotype 1; sofosbuvir and RBV with or without PEG-IFN for 24 weeks in genotypes 2, 3, and 4; or sofosbuvir and RBV for up to 48 weeks in decompensated disease or fibrosing cholestatic hepatitis C.

Simeprevir

Mechanism of Action

Simeprevir is a macrocyclic NS3/4A protease inhibitor that inhibits the HCV NS3/4A protease's cleavage of the HCV polyprotein, preventing viral replication in infected cells.[7]

Approved Indications

The FDA approved the use of simeprevir in combination with PEG-IFN and RBV for HCV genotype 1 infection in treatment-naïve and treatment-experienced patients with noncirrhotic and compensated cirrhotic disease.

A pooled analysis of phase 3 studies of HCV treatment-naïve patients treated with simeprevir for 12 weeks and PEG-IFN/RBV for 24 weeks showed a SVR of 80%. This was reduced to 61% and 60% in patients with interleukin−28B TT genotype and cirrhosis, respectively. The efficacy was also significantly lower among those with genotype 1a who harbor the Q80K polymorphism (SVR 58%).[8, 9]

Prior PEG-IFN/RBV relapsers treated with simeprevir for 12 weeks and PEG-IFN/RBV for 24 weeks had a SVR of 79%.[10] Prior partial- and null-responders treated with simeprevir for 12 weeks and PEG-IFN/RBV for 48 weeks had a SVR of 65% and 53%, respectively.[11]

Table 2 summarizes the approved uses of simeprevir.

Table 2. Recommended Simeprevir Regimens for HCV Genotype 1 Patients

Prior Treatment Status	Medications and Duration	SVR 12
Simeprevir is given orally at 150 mg daily. PEG-IFN is given at 180 μg subcutaneously once per week. RBV is given orally, is weight-based (<75 kg = 1000 mg and >75kg = 1200 mg), and is given in two divided doses daily with food. Patients with renal impairment require an RBV dose reduction.
Naïve	Simeprevir 12 weeks + PEG/RBV 24 weeks	80%
Relapser	Simeprevir 12 weeks + PEG/RBV 24 weeks	79%
Partial	Simeprevir 12 weeks + PEG/RBV 48 weeks	65%
Null	Simeprevir 12 weeks + PEG/RBV 48 weeks	53%

Use Outside the Approved Indications and Conditions

The “Use Outside the Approved Indications” section for sofosbuvir discusses combination therapy of simeprevir with sofosbuvir for patients who are ineligible for PEG-IFN-based therapy, who have renal impairment, or who have recurrent allograft HCV.

Patients who have HIV/HCV coinfection, have genotype 1b, have genotype 1a without Q80K polymorphism, and are on compatible HAART regimens (permitted antiretroviral therapy with simeprevir: raltegravir, rilpivirine, maraviroc, tenofovir, emtricitabine, lamivudine, and abacavir) may consider the following: 1) if no cirrhosis, simeprevir and PEG-IFN/RBV for 12 weeks followed by PEG-IFN/RBV for 12 or 36 weeks based on response-guided therapy criteria; or 2) if cirrhosis, simeprevir and PEG-IFN/RBV for 12 weeks followed by 36 weeks of PEG-IFN/RBV.

Challenges

The challenges associated with the use of these agents include cost of treatment, third-party reimbursement for off-label use, use in special populations, and drug resistance.

Combining direct-acting antiviral agents (DAAs) in an off-label manner may be an attractive option for patients who are unwilling or unable to undergo PEG-IFN-based therapy. While the sofosbuvir/simeprevir strategy relies on phase 2 data supporting safety and efficacy compared with the FDA-approved regimen, these data were derived from exactly those patients who necessitate more urgent treatment (patients with either cirrhosis and bridging fibrosis). It will be of great interest to assess the willingness of third-party payers to support this regimen, especially in the setting of the most recent American Association for the Study of Liver Diseases-Infections Diseases Society of America HCV guidance document, http://www.hcvguidelines.org/ which supports its use.

The optimal use of these medications in special populations such as patients with decompensated cirrhosis, first-generation protease inhibitor failures, recipients of solid organ transplants, and patients with end-stage kidney disease is not clear, because data are much more limited and may be challenging to obtain. Thus, use of these and other DAAs in these populations will likely be off-label and will require justification based on their risk/benefit comparison.

Resistance issues will be clarified as different drugs and combinations are evaluated. One case of sofosbuvir resistance (S282T) was reported in the LONESTAR trial with sofosbuvir and ledipasvir. Although the resistant variant persisted during the retreatment phase with sofosbuvir/ledipasvir/RBV, the patient nonetheless achieved SVR with longer duration of therapy.[12] The efficacy of simeprevir/PEG-IFN/RBV is significantly diminished in patients with genotype 1a who had a baseline Q80K polymorphism; thus, routine baseline Q80K testing should be performed and alternative treatment offered to those with the polymorphism. For those patients treated in the COSMOS trial with sofosbuvir/simeprevir, the baseline Q80K had an insignificant impact on SVR.[13]

Will Sofosbuvir and/or Simeprevir Replace the Previous Generation of Antiviral Agents?

Although there is no head-to-head trial comparison, it appears that simeprevir is at least as effective as telaprevir and boceprevir. Simeprevir has the advantage of once-daily dosing, more tolerable side effects, shorter treatment duration, less intense monitoring, and no requirement to be administered food or a high-fat meal, and this has led to the American Association of the Study of Liver Diseases advising against the use of the first-generation protease inhibitors. In addition, simeprevir is a weak inhibitor of P-glycoprotein and CYP3A4 in the gut; thus, no dose adjustment is required for cyclosporine or tacrolimus, making it a useful treatment agent in the liver transplant recipient.

Sofosbuvir is a potent NS5B polymerase inhibitor that is effective across all HCV genotypes and in difficult-to-treat populations. It is given once daily and is associated with minimal adverse effects. These drugs have the highest barrier to resistance among the current classes and are effective both with and without PEG-IFN. Sofosbuvir has also been associated with promising treatment outcomes as part of an all-oral regimen with other DAAs (e.g., ledipasvir) now completing phase 3 trials.

Overall, sofosbuvir and simeprevir represent a major advance in HCV treatment and will undoubtedly supplant telaprevir and boceprevir based on their efficacy, safety, tolerability, and convenience. While the earliest such drugs are still approved as add-ons to PEG-IFN-based therapy in genotype 1 HCV, all-oral PEG-IFN-free regimens will become available within the next year and will advance HCV treatment even further. (See Table 3 for a summary of key points.)

Table 3. Key Points

• Sofosbuvir and simeprevir, each approved as add-on therapy with PEG-IFN/RBV, have surpassed the previous generation of direct antiviral agents (telaprevir, boceprevir) based on their effectiveness, safety, convenience, and resistance profiles.
• Sofosbuvir is a nucleotide NS5 polymerase inhibitor with pan-genotypic activity and a very high barrier to viral resistance. It has been shown to be effective in treatment-naïve, treatment-experienced, and difficult-to-treat populations such as those with HCV/HIV coinfection, cirrhosis, and patients with mild to moderate impaired renal function and anemia.
• Sofosbuvir is not recommended in patients with severe renal impairment/ESRD or hemodialysis, because no dosing data are currently available for this patient population.
• Simeprevir is a second-wave, macrocyclic NS3/4A protease inhibitor and is effective against HCV genotype 1; however, its clinical efficacy is limited by the Q80K polymorphism in genotype 1a patients.
• Based on phase 2 data, strong rationale exists for the use of sofosbuvir and simeprevir in genotype 1 treatment-naïve or experienced patients with advanced fibrosis who are intolerant of or ineligible for PEG-IFN.
• Sofosbuvir and simeprevir each have minimal to no interaction with cyclosporine and tacrolimus; thus, a combination of sofosbuvir and simeprevir may be considered in the setting of recurrent allograft HCV.
• Given the overall effectiveness and safety of the new HCV therapies, treatment should be strongly considered in each patient to mitigate long-term risks such as disease progression, change in health status making future treatment impossible, and risk of HCV transmission.

References

Source

Regimens Containing Gilead's Sovaldi Have Major Advantages over Other Therapies for Hepatitis C Virus Genotype-3

Gastroenterologists Would Prescribe Sovaldi plus Daclatasvir plus Ribavirin to 60 Percent of Their Genotype-3 Patients, According to Findings from Decision Resources Group

BURLINGTON, Mass., April 1, 2014 /PRNewswire/ -- Decision Resources Group finds that surveyed gastroenterologists in the United States and Europe agree that the percentage of hepatitis C virus (HCV) genotype-3 infected patients with cirrhosis of the liver achieving a sustained virologic response (SVR) is one of the attributes that most influences their prescribing decisions. Clinical data and interviewed experts indicate that interferon-free regimens containing Gilead's Sovaldi (sofosbuvir) and Bristol-Myers Squibb's NS5A inhibitor daclatasvir have convenience and efficacy advantages over currently available regimens for HCV genotype-3 infections. However, competition from other NS5A inhibitors, such as Gilead's GS-5816, may constrain uptake of daclatasvir.

Other key findings from the DecisionBase report entitled Hepatitis C Virus Genotype 3: What Untapped Opportunities Remain for Treatment of Genotype-3 Infections:

• Payer receptivity to new HCV genotype-3 therapies: Almost half of surveyed U.S. managed care organization pharmacy directors would not reimburse a new HCV genotype-3 therapy offering a 6-week duration if priced at $100,000 per course, with a notable share citing price and insufficient clinical benefit as the reasons. This suggests that, assuming comparable efficacy, payers are unwilling to accept a premium for a shorter course of therapy.
• The importance of cost in treatment decisions for HCV genotype-3 infections: Conjoint analysis of drug attributes influencing prescribing behavior revealed that surveyed gastroenterologists perceive the cost of treatment as important as SVR rate in treatment decisions for HCV genotype-3 infected patients. This suggests that the cost of sofosbuvir plus ribavirin is a key barrier to prescribing and that physicians and payers will favor a lower-cost alternative with comparable efficacy and safety.
• Estimated prescribing of the sofosbuvir and daclatasvir combination: Surveyed U.S. gastroenterologists indicated that they would prescribe sofosbuvir and daclatasvir plus ribavirin to 60 percent of their HCV genotype-3 patients.

Comments from Decision Resources Group Analyst Seamus Levine-Wilkinson, Ph.D.:

• "Gilead's interim phase two data for their pangenotypic interferon- and ribavirin-free combination of Sovaldi and the NS5A inhibitor GS-5816 indicates that up to 100 percent of genotype-3 infected patients achieved SVR4. If these impressive results are confirmed in planned phase three studies, likely including evaluation of a coformulated sofosbuvir and GS-5816 one-pill, once-daily regimen, then this combination will provide a highly effective, safe, pangenotypic, and convenient single-tablet regimen for HCV infections. In other words, this could be one pill to rule them all."
• "Cost of HCV therapies is a serious concern among both payers and physicians. Given the high price for a 24-week course of Sovaldi, the new standard of care for HCV genotype-3 infections, it is likely that payers and physicians will be very skeptical of any new HCV genotype-3 therapy priced at a premium to Sovaldi. Conversely, a drug developer that is able to offer a lower-cost interferon- and ribavirin-free regimen for HCV genotype-3 that achieves high SVR rates, will be very well positioned to compete in this market segment."

About Decision Resources Group
Decision Resources Group offers best-in-class, high-value information and insights on critical issues within the healthcare industry. Clients rely on this analysis and data to make informed decisions. Find out more at www.DecisionResourcesGroup.com.

All company, brand, or product names contained in this document may be trademarks or
registered trademarks of their respective holders.

For more information, contact:

Decision Resources Group
Christopher Comfort
781-993-2597
ccomfort@dresourcesgroup.com

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