December 6, 2013

Let the Hep C Drug War Begin

Provided by The Motley Fool

By Brian Orelli | More Articles
December 6, 2013 | Comments

Following Johnson & Johnson's (NYSE:JNJ ) approval of Olysio two weeks ago, Gilead Sciences(NASDAQ: GILD ) gained FDA approval for its hepatitis C drug Sovaldi, previously known by its generic name sofosbuvir.

Let the competition begin.

Unfortunately, it'll likely be short-lived.

Sovaldi is approved to treat four different strains of hepatitis virus referred to as genotype 1-4. Olysio is only approved for genotype 1, so Gilead will have genotype 2-4 all to itself. Johnson & Johnson went after genotype 1 because it's the most prevalent in the U.S.

Both drugs have to be taken with pegylated interferon and ribavirin, the former of which has to be injected and causes flu-like side effects. That's a big deal, especially since the drugs have to be taken for 12 weeks, although it's an improvement on the nearly year-long treatments that were required before oral medications including Vertex Pharmaceuticals' (NASDAQ: VRTX ) Incivek and Merck's (NYSE: MRK ) Victrelis were introduced.

Comparing the clinical trials in the drug labels, Sovaldi has a distinct advantage over Olysio, which isn't recommended for patients with specific genetic change in genotype 1a viruses. And even if you look at patients without the mutation, Olysio only cures 84% of patients compared to 92% for genotype 1a patients taking Sovaldi. Olysio does have a slight advantage for genotype 1b patients with 85% cure rate compared to 82% for Sovaldi. Both drugs appear to be better than Vertex Pharmaceuticals' and Merck's first-generation drugs, which are already starting to be phased out.

Not that it matters much
All oral cocktails that don't require pegylated interferon are on their way. They've produced cure rates as good or better than Gilead's and Johnson & Johnson's combinations. In a phase 3 trial, AbbVie's (NYSE: ABBV ) five-drug combo for instance produced a cure rate of 95% in genotype 1a patients and higher in genotype 1b. Gilead hasn't released phase 3 data for its all-oral combination that'll include Sovaldi, but the phase 2 data looked promising.

Patients whose disease hasn't progressed very far -- hepatitis C acts on the liver over many years -- are likely to wait for the all-oral regimens rather than take Gilead's or Johnson & Johnson's drugs with pegylated interferon.

Or they could just take both (but they won't)
Data from a phase 2 trial combining Olysio and Sovaldi produced solid results with greater than 90% of patients experiencing viral suppression. While the data is very promising, few patients will end up getting the two new medications together since it hasn't been approved by the FDA. Doctors could prescribe the combination off label, but considering the high cost of the two drugs, it's not clear that insurers would pay for it.

And, as was mentioned previously, there's no rush for most patients to get treated. For most patients, doctors will just wait for an FDA-approved all-oral regimen from Gilead or AbbVie rather than risk a combination that hasn't been tested in a larger phase 3 trial.

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Fool contributor Brian Orelli has no position in any stocks mentioned. The Motley Fool recommends Gilead Sciences and Vertex Pharmaceuticals. It recommends and owns shares of Johnson & Johnson. Try any of our Foolish newsletter services free for 30 days. We Fools may not all hold the same opinions, but we all believe that considering a diverse range of insights makes us better investors. The Motley Fool has a disclosure policy.

Source

F.D.A. Approves Pill to Treat Hepatitis C - (New York Times)

By ANDREW POLLACK

Published: December 6, 2013

The Food and Drug Administration on Friday approved a pill that is expected to make the treatment of hepatitis C less onerous, shorter in duration and more effective.

The drug, Sovaldi, from Gilead Sciences, will allow at least some patients infected with the liver-destroying virus to be treated with pills only, doing away with weekly injections of a drug that can have debilitating side effects.

“Today’s approval represents a significant shift in the treatment paradigm for some patients with chronic hepatitis C,” said Dr. Edward Cox, director of the office of antimicrobial products at the F.D.A.

But the greater convenience and effectiveness comes at a price.

Gilead said the wholesale cost of Sovaldi, which is known generically as sofosbuvir, would be $28,000 for four weeks — or $1,000 per daily pill. That translates to $84,000 for the 12 weeks of treatment recommended for most patients, and $168,000 for the 24 weeks needed for a hard-to-treat strain of the virus.

“This is unbearable to the health care system and it is completely unjustified,” said Michael Weinstein, president of the AIDS Healthcare Foundation, which runs treatment clinics in the United States and abroad and has previously clashed with Gilead on the price of its drugs for H.I.V.

The Initiative for Medicines, Access and Knowledge, a legal group based in New York, recently filed a motion to try to block patenting of the drug in India. If it succeeds, generic manufacturers in India will be able to manufacture cheap copies of the drug for distribution there and in some other developing countries.

Gilead said the price was fair given the drug’s higher cure rate and that the total cost for the 12-week regimen was “consistent with, and in some cases lower than” the cost of some other regimens for hepatitis C. It said it would offer financial assistance to some patients.

Some three million to four million Americans, many of them in middle age, are believed to have a chronic hepatitis C infection, though many do not know it. The virus slowly damages the liver, leading to cirrhosis and in some cases to liver cancer. But it often takes decades before any damage is noticeable, and many people never experience a problem.

Globally, at least 150 million people have hepatitis C.

Sovaldi was obtained by Gilead in an $11 billion acquisition of a smaller company, Pharmasset. The high purchase price raised eyebrows when the deal was announced in 2011, but it has vaulted Gilead to the lead in a heated race to develop all-oral treatments for hepatitis C.

AbbVie, Bristol-Myers Squibb, Merck, Johnson & Johnson and others are also developing all-oral regimens for hepatitis C that could reach the market in the next one to three years.

Some analysts expect Sovaldi to become one of the best-selling drugs in the world. Matthew Roden, an analyst at UBS, said in a note on Friday that annual sales could surpass the record of around $13 billion achieved by Lipitor, from Pfizer, in its peak year.

Sales are expected to be strong from the start, because many patients, on the advice of their doctors, have been putting off starting treatment until Sovaldi became available.

One person waiting is Tom Espinosa, a building inspector in Oakland, Calif. He has tried the existing drugs and some experimental ones, without success, so this drug might be his last chance. His liver is already deteriorating badly, but he is hoping the new drug will stop the progression.

Other companies are trying to get at least a little piece of Gilead’s bounty. Merck, Roche and Idenix Pharmaceuticals are separately claiming that Sovaldi infringes on patents they hold. Should any of those companies prevail, it is expected they will receive royalties, not keep the drug off the market.

Until two years ago, the treatment for hepatitis C consisted of 24 to 48 weeks of weekly injections of interferon alfa combined with daily tablets of ribavirin. Neither drug was developed specifically to treat hepatitis C. The combination cured about half of patients, but the side effects, including flulike symptoms, anemia and depression, could be severe.

Sovaldi and newer drugs work by inhibiting enzymes produced by the hepatitis C virus. This is the same approach that was used to make drugs for H.I.V. As in H.I.V., two or more of these drugs for hepatitis C must be used together, to prevent the virus from developing resistance.

Cure rates with Sovaldi, a polymerase inhibitor, are over 80 percent, though success and treatment duration depend in part on which strain, or genotype, of the virus is involved.

For genotypes 2 and 3, which together account for about 20 to 25 percent of cases in the United States, Sovaldi’s label recommends the drug be used with ribavirin. This will constitute the first all-oral, interferon-free treatment for hepatitis C. Genotype 2 will require 12 weeks of treatment and genotype 3 will need 24 weeks.

For genotype 1, which accounts for more than 70 percent of American cases, Sovaldi is supposed to be used with injected interferon and ribavirin. But the treatment is for only 12 weeks instead of 24 or 48, and the cure rate is about 90 percent for newly treated patients.

The label, however, says that genotype 1 patients who are ineligible for interferon can be treated for 24 weeks with Sovaldi and ribavirin. Wall Street analysts had not been expecting an all-oral regimen to be endorsed for genotype 1 patients.

The side effects seem mild, though the clinical trials to date have not been able to distinguish the effects of Sovaldi from the drugs it was taken with.

Ribavirin requires several pills taken more than once a day. Gilead hopes to combine Sovaldi with another drug it is developing into a single pill that can be taken once a day and cure most cases of genotype 1.

Results of clinical trials testing how that combination pill works are expected in the coming weeks. If all goes well, that drug could get to market by the end of next year.

Source

FDA Approves 'Game Changer' Hepatitis C Drug Sofosbuvir

FDA Approvals > Medscape Medical News

Miriam E. Tucker
December 06, 2013

The US Food and Drug Administration (FDA) has approved the first-in-kind nuceotide analog inhibitor sofosbuvir (Sovaldi, Gilead Sciences, Inc) for the treatment of adults with chronic hepatitis C virus (HCV) infection, a widely anticipated move that is expected to dramatically improve outcomes for many patients.

Data presented earlier thisyear at an FDA advisory committee meeting support the use of sofosbuvir in combination with ribavirin (RBV) for all-oral dual therapy of infections with HCV genotypes 2 and 3, as well as in triple therapy along with injected pegylated interferon (pegIFN) and RBV for treatment-naive patients with HCV genotypes 1 and 4.

The availability of the first all-oral, interferon-free regimen is a first and a major advance, experts say.

"This is a very exciting time in liver diseases," Greg Fitz, MD, president of the American Association for the Study of Liver Diseases, said at a news conference held last month during The Liver Meeting 2013, at which sofosbuvir was discussed extensively and new data were presented.

"I think the move away from interferon and toward a high probability of success is remarkably encouraging for all of us.... Suddenly, it's realistic to think we can cure most patients with hepatitis C," Dr. Fitz told reporters.

"Sofosbuvir is a game-changer and will allow high cure rates with just 12-week regimens," David R. Nelson, MD, assistant vice president for research, professor of medicine, and associate dean of clinical research at the College of Medicine, University of Florida, Gainesville, told Medscape Medical News.

Indeed, liver expert Norah A. Terrault, MD, told Medscape Medical News that sofosbuvir holds numerous advantages over current therapy because of its efficacy profile, safety, and tolerability across many different patient populations and HCV genotypes, as well as its dosing simplicity.

"And of course, the first all-oral option for patients with HCV is also a large step forward in terms of principal, to show that you can eradicate HCV without interferon being part of the treatment cocktail.... It's a huge and major advance," said Dr. Terrault, professor of medicine and surgery and director of the Viral Hepatitis Center at the University of California, San Francisco.

Data supporting licensure for sofosbuvir came from 6 clinical trials consisting of 1947 participants, some in trials of sofosbuvir plus RBV with HCV genotype 2 or 3 (including both treatment-naive patients and those who had failed or could not tolerate previous therapy) and others taking the triple combination of sofosbuvir, RBV, and pegIFN in 3 treatment-naive patients infected with HCV genotypes 1, 4, 5, or 6.

At the advisory committee hearing, Gilead scientists reported sustained viral clearance at 12 weeks (SVR12) ranging from 89% to 95% for genotype 2 and 61% to 63% for genotype 3. For HCV genotype 1, which accounts for about 70% of all HCV in the United States, sofosbuvir-based triple therapy including pegIFN produced an SVR12 of 89%.

Dr. Terrault noted that although there has been a published trial showing efficacy of sofosbuvir and RBV without IFN for HCV genotype 1, the SVR12 was inferior to the triple therapy regimen.

New Treatment Options

Dr. Terrault suggested that patients with HCV genotypes 2 and 3 who have been "warehoused" waiting for the new sofosbuvir-based regimens can begin treatment immediately.

For HCV genotypes 1, 4, and 6, whether or not to begin using sofosbuvir-based therapy depends on the situation. For patients who do not have severe liver disease, waiting is still an option.

At least 4 companies are working on interferon-free regimens that are expected to be available for genotype 1. "We're not talking 10 years away, we're talking about 18 months," she told Medscape Medical News.

"Unless a patient has advanced liver disease, one has the luxury of time to wait for good therapies to come forward, to find the right one for the patient…. With this very rapidly evolving field of therapeutics, we should be thoughtful about when we intervene. We should be doing it with the goal of treating them once and with the highest likelihood of success. And we know that over the next couple of years, the proportion that's going to be successful will go up and the ease of treatment will be increased," Dr. Terrault predicted.

However, for patients with genotype 1 who have advanced liver disease (stage 3 or 4), the triple combination of sofosbuvir/IFN/RBV is now an option, as is the off-label combination of sofosbuvir plus the newly licensed simeprevir.

Dr. Terrault noted that although the ultimate goal is to move toward IFN-free regimens, IFN does have the advantage of shortening the treatment time to just 12 weeks. "There's a lot of enthusiasm for IFN-free, and for sure it's the way the field is going...but in the interim we have sofosbuvir for genotype 1 approved with pegIFN and RBV, so it's reasonable to discuss that option."

Dr. Nelson pointed out that although the combination of sofosbuvir with simeprevir (with or without ribavirin) is not yet FDA-approved, phase 2 data presented at The Liver Meeting showed SVR12 rates greater than 90% in genotype 1 patients.

"Given the recent...phase 2 data, there will be great interest to combine sofosbuvir and simeprevir in all-oral regimens for genotype 1 patients. This may also be the preferred regimen for post-liver transplant," he told Medscape Medical News.

Cost Considerations

Addressing the issue of cost, announced to be about $80,000 per treatment course, Dr. Terrault said it is important to factor in other contributors such as additional monitoring and treatment of adverse effects that are expected to be lower with sofosbuvir. "It's not just a matter of cost per pill.... The cost per cure is what you want to see."

In a study presented at The Liver Meeting, the cost per SVR of current telaprevir-based triple therapy at 1 institution was calculated to be $189,000.

Dr. Terrault told Medscape Medical News, "There will be a competitive market of all-oral drugs in the future. I would predict that as the years go by and we have more all-oral combinations coming to market, it will ultimately result in less expensive options for patients. It may not be in the next year, but over time it will help to have therapy become less costly and maybe then more broadly applicable, not just in the US but in terms of the world market."

Dr. Fitz has disclosed no relevant financial relationships. Dr. Nelson has research relationships with both Gilead and Janssen. Dr. Terrault has received grant support from Gilead, Novartis, and Abbvie and has consulted for BMS and Janssen.

Source

AHF: Gilead Outrage on Hep C Drug Price!

$84,000 for a twelve week supply of Sovaldi, Gilead’s new Hepatitis C drug, (sofosbuvir), which was approved Friday by the F.D.A.—$1,000 a pill!

Drug is only one portion of a two drug, twelve-week combination treatment for hepatitis; Gilead’s predatory history of price gouging on lifesaving medications sets stage for action from government officials and drug purchasers for government programs to compel Gilead to cut pricing.

December 06, 2013 05:49 PM Eastern Standard Time

WASHINGTON--(BUSINESS WIRE)--AIDS Healthcare Foundation (AHF), the nation’s largest HIV/AIDS nonprofit medical provider, expressed its profound outrage at Gilead Sciences over the price of Sovaldi, its new Hepatitis C drug, which was approved by the Food and Drug Administration (FDA) on Friday. Gilead set the price at $84,000 Wholesale Acquisition Cost (WAC) for a twelve-week supply of the drug--$1,000 per pill. The drug, known during drug trials as GS-7977 (sofosbuvir), is one component of a two-drug, twelve-week combination treatment for Hepatitis C, which affects an estimated 3.2 million people in the United States.

“For Gilead, we have outrage, pure and simple”

“For Gilead, we have outrage, pure and simple,” said Michael Weinstein, President of AIDS Healthcare Foundation. “There can be no better example of the unbridled greed of the pharmaceutical industry than Gilead’s latest move: pricing its new hepatitis drug at $84,000 per 28-tablet bottle or $1,000 per pill! Gilead’s predatory pricing of Sovaldi is a direct threat to public heath, and it sets the stage for legislators and advocates to demand that officials who purchase drugs for government programs like Medicaid, Medicare and the AIDS Drug Assistance Programs act decisively to rein in pricing and protect patient access to lifesaving medications.”

MEDIA AVAILABILITY: AHF to comment on FDA approval, and Gilead’s pricing, of its new Hepatitis C drug, Sovaldi (sofosbuvir).

WHO: Michael Weinstein, President, AIDS Healthcare Foundation

CONTACT: Ged Kenslea, AHF Communications +1.323.791.5526 mobile

AIDS Healthcare Foundation (AHF), the largest global AIDS organization, currently provides medical care and/or services to more than 260,000 individuals in 32 countries worldwide in the US, Africa, Latin America/Caribbean, the Asia/Pacific Region and Eastern Europe. To learn more about AHF, please visit our website: www.aidshealth.org, find us on Facebook: www.facebook.com/aidshealth and follow us on Twitter: @aidshealthcare

Contacts

AIDS Healthcare Foundation
Ged Kenslea
Communications Director
Work: 323-308-1833
Cell: 323-791-5526
gedk@aidshealth.org
or
Tom Myers
General Counsel & Chief of Public Affairs
Work: 323-860-5259
tom.myers@aidshealth.org

Source

Patient Assistance for Sovaldi™ (sofosbuvir)

Gilead

Excerpt …

U.S. Patient Assistance Program

Gilead is committed to ensuring that people with hepatitis C can access Sovaldi and has launched Support Path™ (www.MySupportPath.com) to provide assistance to patients who are uninsured, underinsured or who need financial assistance to pay for the medicine. The program consists of an integrated offering of support services for patients and providers, including:

  • Access to dedicated case managers to help patients and their providers with insurance-related needs, including identifying alternative coverage options such as federally-insured programs (e.g., Medicaid, Medicare) and health exchanges.
  • Education and support, including a 24/7 nursing support service line and the ability to schedule an onsite visit from a clinical educator.
  • The Sovaldi Co-pay Coupon Program, which provides co-pay assistance for eligible patients with private insurance who need assistance paying for out-of-pocket medication costs. Most patients will pay no more than $5 per co-pay. Co-pay assistance can also be applied toward deductibles and co-insurance obligations.
  • Gilead will provide support to the Patient Access Network (PAN) Foundation, an independent non-profit organization that provides assistance for eligible federally-insured and privately-insured patients who need help covering out-of-pocket medication costs.
  • The Support Path Patient Assistance Program will provide Sovaldi at no charge for eligible patients with no other insurance options.

Information about how to apply for any of these forms of assistance can be found at www.MySupportPath.com or by calling 1-855-7MyPath (1-855-769-7284) between 9 a.m. - 8 p.m. EST.

Source

Gilead

– Sovaldi Approved for Use in Genotypes 1, 2, 3 or 4 –

– High Cure Rates (SVR12) and Shortened, 12-Week Course of Therapy for Many Patients –

– First Ever Oral Treatment Regimen for Genotypes 2 or 3 –

– First Regimen for Patients Awaiting Liver Transplantation to Prevent HCV Recurrence –

FOSTER CITY, Calif.--(BUSINESS WIRE)--Dec. 6, 2013-- Gilead Sciences, Inc. (Nasdaq: GILD) today announced that the U.S. Food and Drug Administration (FDA) has approved Sovaldi™ (sofosbuvir) 400 mg tablets, a once-daily oral nucleotide analog polymerase inhibitor for the treatment of chronic hepatitis C (CHC) infection as a component of a combination antiviral treatment regimen. Sovaldi’s efficacy has been established in subjects with hepatitis C virus (HCV) genotypes 1, 2, 3 or 4 infection, including those with hepatocellular carcinoma meeting Milan criteria (awaiting liver transplantation) and those with HCV/HIV-1 co-infection. Recommended regimens and treatment duration for Sovaldi combination therapy in HCV mono-infected or HCV/HIV-1 co-infected patients follows:

Treatment         Duration
Genotype 1 or 4        

Sovaldi + peg-interferon alfa
+ ribavirin

        12 weeks
Genotype 2         Sovaldi + ribavirin         12 weeks
Genotype 3         Sovaldi + ribavirin         24 weeks
               

Sovaldi in combination with ribavirin for 24 weeks can be considered for CHC patients with genotype 1 infection who are interferon ineligible. Additionally, Sovaldi should be used in combination with ribavirin for treatment of CHC patients with hepatocellular carcinoma awaiting liver transplantation for up to 48 weeks or until liver transplantation to prevent post-transplant HCV infection. Treatment regimen, duration and response to Sovaldi are dependent on viral genotype and patient population, and associated baseline factors. Monotherapy is not recommended. Full Prescribing Information will be available on www.Gilead.com.

The FDA granted Sovaldi Priority Review and Breakthrough Therapy designation, which is granted to investigational medicines that may offer major advances in treatment over existing options.

“I believe that Sovaldi will have a major impact on public health by significantly increasing the number of Americans who are cured of hepatitis C,” said Ira Jacobson, MD, Chief of the Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York City and a principal investigator in the Sovaldi clinical trials. “In clinical studies, Sovaldi in combination with other agents achieved very high cure rates while shortening the duration of treatment to as little as 12 weeks and reducing or completely eliminating the need for interferon injections, depending on the viral genotype.”

Chronic hepatitis C affects an estimated 4 million people in the United States, the majority of whom are “baby boomers” – individuals born between 1945 and 1965. The disease is the nation’s leading cause of liver cancer and liver transplantation, and in recent years has surpassed HIV/AIDS as a cause of death. The current standard of care for HCV involves up to 48 weeks of therapy with a pegylated interferon (peg-IFN)/ribavirin (RBV)-containing regimen, which may not suitable for certain types of patients.

“It is our hope that Sovaldi will mark the beginning of a new era in hepatitis C treatment. Gilead is proud to have played a role in bringing about this important therapeutic advance and we would like to extend our thanks to the many patients and physicians who partnered with us on Sovaldi’s clinical studies,” said John C. Martin, PhD, Chairman and Chief Executive Officer, Gilead Sciences.

Sovaldi’s approval is supported primarily by data from four Phase 3 studies, NEUTRINO, FISSION, POSITRON and FUSION, which evaluated 12 or 16 weeks of treatment with Sovaldi combined with either RBV or RBV plus peg-IFN. Three of these studies evaluated Sovaldi plus RBV in genotype 2 or 3 patients who were either treatment-naïve (FISSION), treatment-experienced (FUSION) or peg-IFN intolerant, ineligible or unwilling (POSITRON). NEUTRINO evaluated Sovaldi in combination with Peg-IFN/RBV in treatment naïve patients with genotypes 1, 4, 5 or 6. In these studies, Sovaldi-based therapy was found to be superior to historical controls (NEUTRINO and FUSION) or to placebo (POSITRON), or non-inferior to currently available treatment options (FISSION) based on the proportion of patients who had a sustained virologic response (HCV undetectable) 12 weeks after completing therapy (SVR12). Patients who achieve SVR12 are considered cured of HCV. Trial participants taking Sovaldi-based therapy achieved SVR12 rates of 50-90 percent. For full study details, see the Clinical Studies section of the full Prescribing Information.

During the FDA’s review, data from two additional Phase 3 studies, VALENCE and PHOTON-1, were added to the NDA as a result of the Breakthrough Designation status. In the VALENCE study, patients with genotype 3 HCV infection were treated with Sovaldi and RBV for 24 weeks. Eighty-four percent of patients in this trial achieved SVR12. The PHOTON-1 study evaluated Sovaldi and RBV for 12 weeks in patients with genotype 2 HCV infection co-infected with HIV-1 and for 24 weeks in patients with genotypes 1 or 3 HCV co-infected with HIV-1. Trial participants achieved SVR12 rates of 76-92 percent. In all Phase 3 studies of Sovaldi, no viral resistance to the drug was detected among patients who relapsed following completion of therapy.

To date, nearly 3,000 patients have received at least one dose of Sovaldi in Phase 2 or 3 studies. Sovaldi combination therapy was well tolerated in clinical studies. Adverse events were generally mild and there were few treatment discontinuations due to adverse events. The most common adverse events occurring in at least 20 percent of patients receiving Sovaldi in combination with Peg-IFN/RBV were fatigue, headache, nausea, insomnia and anemia; see below for Important Safety Information regarding contraindications, warnings and precautions, adverse reactions and drug interactions.

On November 22, 2013, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) issued a positive opinion on Gilead’s application for marketing authorization for Sovaldi. The CHMP opinion was adopted following an accelerated review procedure, which is reserved for medicinal products that are expected to be of major public health interest. This assessment does not guarantee marketing authorization by the European Commission. If approved, Sovaldi could be available in the European Union in the first quarter of 2014. Applications for marketing approval of Sovaldi are also pending in Australia, Canada, New Zealand, Switzerland and Turkey.

Dr. Jacobson is a paid consultant to Gilead.

The Wholesaler Acquisition Cost (WAC) of a 28-tablet bottle of Sovaldi in the United States is $28,000.

U.S. Patient Assistance Program

Gilead is committed to ensuring that people with hepatitis C can access Sovaldi and has launched Support Path™ (www.MySupportPath.com) to provide assistance to patients who are uninsured, underinsured or who need financial assistance to pay for the medicine. The program consists of an integrated offering of support services for patients and providers, including:

  • Access to dedicated case managers to help patients and their providers with insurance-related needs, including identifying alternative coverage options such as federally-insured programs (e.g., Medicaid, Medicare) and health exchanges.
  • Education and support, including a 24/7 nursing support service line and the ability to schedule an onsite visit from a clinical educator.
  • The Sovaldi Co-pay Coupon Program, which provides co-pay assistance for eligible patients with private insurance who need assistance paying for out-of-pocket medication costs. Most patients will pay no more than $5 per co-pay. Co-pay assistance can also be applied toward deductibles and co-insurance obligations.
  • Gilead will provide support to the Patient Access Network (PAN) Foundation, an independent non-profit organization that provides assistance for eligible federally-insured and privately-insured patients who need help covering out-of-pocket medication costs.
  • The Support Path Patient Assistance Program will provide Sovaldi at no charge for eligible patients with no other insurance options.

Information about how to apply for any of these forms of assistance can be found at www.MySupportPath.com or by calling 1-855-7MyPath (1-855-769-7284) between 9 a.m. - 8 p.m. EST.

Global Availability

Gilead is committed to helping ensure access to Sovaldi in resource-limited settings. The company is developing a hepatitis C treatment access program, focusing on those countries with the greatest HCV burden. Full program details will be announced in the coming months.

About Sovaldi

Sovaldi is an oral nucleotide analog inhibitor of the HCV NS5B polymerase enzyme, which plays an essential role in HCV replication. Sovaldi is a direct-acting agent, meaning that it interferes directly with the HCV life cycle by suppressing viral replication. Treatment regimen and duration for Sovaldi are dependent on both viral genotype and patient population. Treatment response varies based on baseline host and viral factors. Monotherapy is not recommended for treatment of CHC.

IMPORTANT SAFETY INFORMATION

Contraindications

Sovaldi combination treatment with ribavirin or with peginterferon alfa plus ribavirin is contraindicated in women who are pregnant or may become pregnant and men whose female partners are pregnant because of the risk for birth defects and fetal death associated with ribavirin. Contraindications to peginterferon alfa and ribavirin also apply to Sovaldi combination treatment. Refer to the prescribing information of peginterferon alfa and ribavirin for a list of their contraindications.

Warnings and Precautions

  • Pregnancy: Use with Ribavirin or Peginterferon Alfa/Ribavirin: Ribavirin therapy should not be started unless a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Female patients of childbearing potential and their male partners must use two forms of non-hormonal contraception during treatment and for at least 6 months after treatment has concluded. Routine monthly pregnancy tests must be performed during this time. Refer to the prescribing information for ribavirin.
  • Use with Potent P-gp Inducers: Rifampin and St. John’s wort should not be used with Sovaldi as they may significantly decrease sofosbuvir plasma concentration, reducing its therapeutic effect.

Adverse Reactions

Most common (≥20%, all grades) adverse reactions for:

  • Sovaldi + peginterferon alfa + ribavirin combination therapy were fatigue, headache, nausea, insomnia, and anemia
  • Sovaldi + ribavirin combination therapy were fatigue, and headache

Drug Interactions

In addition to rifampin and St. John’s wort, coadministration of Sovaldi is not recommended with carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifapentine, and tipranavir/ritonavir. Such coadministration is expected to decrease the concentration of sofosbuvir, reducing its therapeutic effect.

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 physicians and patients may not see advantages of Sovaldi over other therapies and may therefore be reluctant to prescribe the product, and the risk that public payers may be reluctant to approve or provide reimbursement for the product. In addition, pending marketing applications for Sovaldi in the European Union and other territories may not be approved in the currently anticipated timelines or at all, and marketing approval, 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 Quarterly Report on Form 10-Q for the quarter ended September 30, 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 and Support Path are trademarks or registered trademarks 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.

Photos/Multimedia Gallery Available: http://www.businesswire.com/multimedia/home/20131206005775/en/

Source: Gilead Sciences, Inc.

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

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FDA approves Sovaldi (Sofosbuvir) for chronic hepatitis C

FDA NEWS RELEASE

For Immediate Release: Dec. 6, 2013

Media Inquiries: Stephanie Yao, 301-796-0394, stephanie.yao@fda.hhs.gov

Consumer Inquiries: 888-INFO-FDA

FDA approves Sovaldi for chronic hepatitis C

Drug is third with breakthrough therapy designation to receive FDA approval

The U.S. Food and Drug Administration today approved Sovaldi (sofosbuvir) to treat chronic hepatitis C virus (HCV) infection. Sovaldi is the first drug that has demonstrated safety and efficacy to treat certain types of HCV infection without the need for co-administration of interferon.

“Today’s approval represents a significant shift in the treatment paradigm for some patients with chronic hepatitis C,” said Edward Cox, M.D., director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research.

Sovaldi is the second drug approved by the FDA in the past two weeks to treat chronic HCV infection. On November 22, the FDA approved Olysio (simeprevir).

Hepatitis C is a viral disease that causes inflammation of the liver that can lead to diminished liver function or liver failure. Most people infected with HCV have no symptoms of the disease until liver damage becomes apparent, which may take several years. Some people with chronic HCV infection develop scarring and poor liver function (cirrhosis) over many years, which can lead to complications such as bleeding, jaundice (yellowish eyes or skin), fluid accumulation in the abdomen, infections or liver cancer. According to the Centers for Disease Control and Prevention, about 3.2 million Americans are infected with HCV.

Sovaldi is a nucleotide analog inhibitor that blocks a specific protein needed by the hepatitis C virus to replicate. Sovaldi is to be used as a component of a combination antiviral treatment regimen for chronic HCV infection. There are several different types of HCV infection. Depending on the type of HCV infection a patient has, the treatment regimen could include Sovaldi and ribavirin or Sovaldi, ribavirin and peginterferon-alfa. Ribavirin and peginterferon-alfa are two drugs also used to treat HCV infection.

Sovaldi’s effectiveness was evaluated in six clinical trials consisting of 1,947 participants who had not previously received treatment for their disease (treatment-naive) or had not responded to previous treatment (treatment-experienced), including participants co-infected with HCV and HIV. The trials were designed to measure whether the hepatitis C virus was no longer detected in the blood at least 12 weeks after finishing treatment (sustained virologic response), suggesting a participant’s HCV infection has been cured.

Results from all clinical trials showed a treatment regimen containing Sovaldi was effective in treating multiple types of the hepatitis C virus. Additionally, Sovaldi demonstrated efficacy in participants who could not tolerate or take an interferon-based treatment regimen and in participants with liver cancer awaiting liver transplantation, addressing unmet medical needs in these populations.

The most common side effects reported in clinical study participants treated with Sovaldi and ribavirin were fatigue and headache. In participants treated with Sovaldi, ribavirin and peginterferon-alfa, the most common side effects reported were fatigue, headache, nausea, insomnia and anemia.

Sovaldi is the third drug with breakthrough therapy designation to receive FDA approval. The FDA can designate a drug as a breakthrough therapy at the request of the sponsor if preliminary clinical evidence indicates the drug may demonstrate a substantial improvement over available therapies for patients with serious or life-threatening diseases. Sovaldi was reviewed under the FDA’s priority review program, which provides for an expedited review of drugs that treat serious conditions and, if approved, would provide significant improvement in safety or effectiveness.

Sovaldi is marketed by Gilead, based in Foster City, Calif. Olysio is marketed by Raritan, N.J.-based Janssen Pharmaceuticals.

For more information:

FDA: Approved Drugs: Questions and Answers

FDA: Drug Innovation

FDA: What’s New at FDA in Hepatitis

CDC: Hepatitis C Information for the Public

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

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Gilead’s (GILD) Blockbuster Hep C Drug Ready for Launch

Provided by Cabot Investing Advice

on December 06, 2013

Gilead Sciences' (GILD) hepatitis C treatment Sovaldi, formerly known as sofosbuvir, is one of the most anticipated new drugs in the industry in quite some time. Everyone and his mother expect the FDA to approve it by its Sunday deadline, thanks to the strong safety and efficacy data produced in its clinical trials.

Analysts are modeling an already-blockbuster $1.7 billion in sales next year, climbing to $8 billion in 2018, making it one of the best-selling drugs in the world.

Expectations are so high because Sovaldi promises substantial improvement on existing treatments for a serious disease. It's both more effective and has fewer side effects than the standard regimen of pegylated interferon, and it can be swallowed rather than injected.

The only live question at this point is where Gilead will price the drug. ISI Group analyst Mark Schoenebaum's informal survey of buy-side analysts last month found an average estimate of $85,000 for 12 weeks of treatment, but sell-side estimates have been running as high as $100,000. The price depends partly on how the FDA chooses to label the drug, which remains to be seen.
GILD is a Cabot Top Ten Trader stock.

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J Acquir Immune Defic Syndr. 2013 Dec 15;64(5):434-42. doi: 10.1097/QAI.0b013e3182a06eb6.

Fernández-Rodríguez A, Berenguer J, Jiménez-Sousa MA, Guzmán-Fulgencio M, Micheloud D, Miralles P, López JC, Bellón JM, Aldamiz-Echevarria T,García-Broncano P, Carrero A, Alvarez E, Resino S.

*Viral Infection and Immunity Unit, National Centre of Microbiology, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain; †Infectious Diseases and HIV Unit, Hospital General Universitario Gregorio Marañón, Madrid, Spain; ‡Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain; and Departments of §Internal Medicine; ‖Pathology, Hospital General Universitario, Gregorio Marañón, Madrid, Spain.

Abstract

OBJECTIVE: To assess the ability of the cirrhosis risk score (CRS) to predict liver fibrosis progression in HIV/hepatitis C virus (HCV)-coinfected patients.

DESIGN: Retrospective follow-up study.

METHODS: Based on a minimum follow-up time of 10 years with HCV infection, 190 HIV/HCV-coinfected patients were classified according to their METAVIR score: (1) 25 nonprogressor patients who did not develop fibrosis (F0) and (2) 165 progressor patients who developed fibrosis (F ≥ 1). Seven polymorphisms of CRS signature and IL28B genotype were performed using the GoldenGate assay. The CRS signature was calculated by naive Bayes formula as previously described.

RESULTS: Nonprogressors had CRS values significantly lower than progressors (0.61 versus 0.67; P = 0.043). Among the progressors, we observed similar CRS values through all the fibrosis stages (F1/F2/F3/F4). The percentage of patients with CRS > 0.70 (high risk of developing fibrosis) was higher in progressors than in nonprogressors; but the percentages with values between 0.50 and 0.70 (intermediate risk) and <0.50 (low risk) were quite similar for each of the fibrosis stages (P = 0.047). The area under the receiver-operating characteristic curve of CRS for discriminating nonprogressor versus progressor was 0.625 (P = 0.043). When clinical variables were considered (age at HCV infection, intravenous drug use, gender, IL28B, and HCV genotype), the area under the receiver-operating characteristic curve of CRS improved up to 0.739 (P < 0.001).

CONCLUSIONS: CRS itself seems not to be a good marker for identifying HIV/HCV-coinfected patients who are at high risk of developing liver fibrosis. However, CRS score coupled with clinical factors might help to distinguish between nonprogressors and progressors patients.

PMID: 23797694 [PubMed - in process]

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Journal of Gastroenterology and Hepatology

Special Issue: Third Asian-Pacific Topic Conference (APTC2012): Nutrition-related disorders and digestive system. Organized by Japanese Society of Gastroenterology (JSGE) and Asian-Pacific Association of Gastroenterology (APAGE), Tokyo, Japan, November 2–3, 2012. Guest Editor: Soichiro Miura

Volume 28, Issue Supplement S4, pages 93–98, December 2013

Nutrition-Related Liver Disorders: NAFLD

You have free access to this content

Keisuke Hino*, Sohji Nishina, Yuichi Hara

Article first published online: 19 NOV 2013

DOI: 10.1111/jgh.12243

© 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd

Keywords: hepatitis C;  hepcidin;  iron;  oxidative stress;  reactive oxygen species

Abstract

The liver is the major iron storage organ in the body, and therefore, iron metabolic disorder is sometimes involved in chronic liver diseases. Chronic hepatitis C is one of the liver diseases that show hepatic iron accumulation, even though its level should be recognized to be basically mild to moderate and sometimes within the normal range. The mechanisms underlying hepatic iron accumulation in chronic hepatitis C have not been fully elucidated. Reduction of the hepcidin transcription activity by hepatitis C virus (HCV)-induced reactive oxygen species may in part account for it, but the regulation of hepcidin is very complex and may depend on many variables, including the particular stage of the systemic and/or hepatic inflammatory conditions and the circulating transferrin-bound iron and intracellular iron stores. This might explain the variations in hepatic iron concentrations reported among patients with HCV-related chronic liver disease. However, even mild-to-moderate iron overload in the liver contributes to disease progression and hepatocarcinogenesis in chronic hepatitis C probably by reinforcing the HCV-induced oxidative stress through Fenton reaction. The present review highlights the current concept of hepatic iron overload status in chronic hepatitis C and discusses how iron metabolic disorder develops in this disease and the impact of hepatic iron overload on disease progression and its relevance to hepatocarcinogenesis.

Introduction

Approximately 170 million people worldwide are infected with hepatitis C virus (HCV).[1] HCV infection often remains asymptomatic but can lead to severe liver damage. However, how HCV causes liver injury and liver cancer is not fully understood. Histological examination has revealed that chronic inflammation seems to play an important role in the pathogenesis of chronic hepatitis C, and excess iron also is associated with increased morbidity and mortality.[2, 3] In addition, a study using electron microscopy and X-ray microanalysis demonstrated that almost all liver specimens from patients with chronic hepatitis C had at least some lysosomal iron deposits even when no iron deposit was evident with standard optical microscopy and Prussian Blue staining.[4] Elevated iron-related serum markers and increased hepatic iron accumulation are relatively common and correlate with the severity of hepatic inflammation and fibrosis in patients with chronic hepatitis C. Excess divalent iron can be highly toxic mainly via the Fenton reaction producing hydroxyl radicals.[5] This is particularly relevant for chronic hepatitis C, in which oxidative stress has been proposed as a major mechanism of liver injury. Oxidative stress and increased iron levels strongly favor DNA damage, genetic instability, and tumorgenesis. Indeed, a significant correlation between 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of oxidatively generated DNA damage,[6] and hepatic iron excess has been shown in patients with chronic hepatitis C.[7] Kato et al. reported that phlebotomy lowered the risk of progression to hepatocellular carcinoma (HCC),[8, 9] which showed the critical role of iron in the development of HCC in patients with chronic hepatitis C. Thus, there is a critical interaction between HCV infection and hepatic iron overload in the progression of liver disease and the development of HCV-related HCC. However, the mechanisms underlying hepatic iron overload and its contribution to hepatocarcinogenesis in chronic hepatitis C are not fully elucidated. The present review highlights the current concept of hepatic iron overload status in chronic hepatitis C and discusses how iron metabolic disorder develops in chronic hepatitis C, the impact of hepatic iron overload on disease progression, and its relevance to hepatocarcinogenesis.

Regulation of systemic iron homeostasis

In normal adults, storage iron is deposited in hepatocytes and tissue macrophages and mobilized in response to acute need. Serum iron levels are determined both by intestinal absorption and macrophage recycling of iron from hemoglobin because there is no efficient pathway for iron excretion.[10] Regulatory effectors that modulate intestinal iron absorption probably also modulate the release of iron from tissue macrophages and hepatocytes. Hepcidin appears to be such a regulatory effector. It is a small, cysteine-rich peptide, cleaved from a larger precursor.[11-13] Hepcidin, which was originally isolated from human serum and urine as a peptide with antimicrobial activity,[11, 13] is a hormone exclusively synthesized in the liver and a soluble regulator that acts to attenuate both intestinal iron absorption and iron release from reticuloendothelial macrophages.[12, 14] Increased plasma iron from macrophage recycling of aged red blood cells or from intestinal absorption of iron stimulates hepatocytes through several signaling pathways to produce more hepcidin. Ferroportin is an iron exporter on the surface of absorptive intestinal enterocytes, macrophages, hepatocytes, and placental cells, all of which release iron into plasma.[15-17] Circulating hepcidin can bind to ferroportin, cause internalization, and trap iron in hepatocytes, macrophages, and absorptive enterocytes.[18] Thus, coupling the internalization of ferroportin to hepcidin levels generates a homeostatic loop regulating the iron plasma level and the tissue distribution of iron.

Transcriptional regulation of hepcidin

Knowledge of how hepcidin transcription is regulated within hepatocytes appears to be indispensable for understanding the mechanisms underlying hepatic iron overload in chronic hepatitis C because hepcidin is the central regulator of systemic iron homeostasis. Important elements of the signaling pathway present on the hepatic plasma membrane that affect hepcidin transcription include transferrin receptor 2 (TfR2),[19] HFE,[20] which is the protein affected in the most common form of genetic hemochromatosis, and hemojuverin (HJV),[21] a member of the bone morphogenetic protein (BMP) receptor family. The mechanisms by which TfR2, HFE, and HJV are linked to changes in hepcidin transcription are incompletely understood, but the discovery of HJV revealed that the well-known sons of mothers against decapentaplegic (SMAD) signal transduction pathway was important in this process.[22] Notably, animals that lack hepatocyte SMAD4, a protein that combines with other members of the SMAD family to regulate transcription of target genes, develop significant iron overload associated with a profound reduction in hepcidin expression.[23] Interleukin 6 (IL-6) activates hepcidin transcription through a pathway that involves janus kinase-signal transducer and activator of transcription (STAT) signaling and a binding site for the transcription factor STAT3.[24, 25] The transcription factor CCAAT/enhancer-binding protein α (C/EBPα) is also clearly involved in regulating hepcidin transcription.[26] C/EBPα knockout mice demonstrate decreased hepcidin expression and iron overload.[26]

The pathways described earlier activate hepcidin transcription, but only one pathway has been identified that represses hepcidin expression. The transmembrane serine protease (TMPRSS6) is part of the pathway that suppresses hepcidin expression as revealed in TMPRSS6 mutant mice.[27]

Hepatic iron accumulation in chronic hepatitis C

Based on the assumption that one-third of iron stores are normally in the liver, this would translate to a normal median hepatic iron content of 0.27 g for men and 0.13 g for women.[28] Extensive studies reported median hepatic iron concentrations of 396 (range 0–2105) and 458 (range 114–2190) μg/g dry weight liver tissue in patients with chronic hepatitis C.[29, 30] These results suggest that hepatic iron content in patients with chronic hepatitis C is approximately 0.50∼0.69 g, equivalent to two to five times the normal hepatic iron content if the liver weight is estimated to be 1500 g. In contrast, a hepatic iron index (μmol Fe/g liver tissue/patients age) of 1.9 or more has been reported to be typical of patients with hereditary hemochromatosis.[31] If the hepatic iron index of a patient aged 60 with hereditary hemochromatosis is 1.9, the hepatic iron concentration of this patient is assumed to be 6384 μg/g liver tissue. Thus, we should understand that hepatic iron content is much less in chronic hepatitis C than in hereditary hemochromatosis, even though it is recognized to be one of liver diseases that show hepatic iron accumulation.

There also remains uncertainty as to whether iron predominantly accumulates in hepatocytes or the reticuloendothelial system, mainly Kupffer cells, in patients with chronic hepatitis C. Some clinical studies showed that iron was mainly localized in the reticuloendothelial system,[32, 33] whereas others reported its localization in hepatocytes.[34] Interestingly, Fiel et al. documented that even ribavirin-associated hemolysis deposited iron preferentially in hepatocytes in patients with chronic hepatitis C.[35] Hepatocytic iron accumulation may indicate potential DNA damage and genetic instability in association with HCV-induced oxidative stress, whereas iron deposition in Kupffer cells may contribute to cytokine release leading to inflammation or fibrosis. However, further investigations are needed to clarify this issue.\

Mechanisms underlying hepatic iron accumulation in chronic hepatitis C

HFE is a major histocompatibility class I-like (MHC) molecule that, unlike other known classical and non-classical MHC proteins, has a regulatory role in the functions of iron metabolism in cells and the body. A homozygous mutation in the HFE protein in humans that changes cysteine at position 282 to tyrosine is responsible for iron overload and organ damage resulting in hemochromatosis.[36] The role of HFE mutations in chronic hepatitis C has been well reviewed.[37] In general, patients with chronic hepatitis C seem to have no difference in the prevalence of heterozygosity for HFE mutations as compared with a control population. It is still controversial as to whether HFE mutations are associated with hepatic iron overload in chronic hepatitis C probably because of the different methodologies used to measure hepatic iron and/or confounding variables such as demographic parameters, environmental factors, hepatic inflammatory activity, and the duration of HCV infection among the reported studies. In addition, HFE mutations are seemingly not associated with the progression of liver disease in chronic hepatitis C patients even though HFE may affect Kupffer cells or interact with immune cells.

Fujita et al. showed for the first time that hepatic hepcidin messenger RNA (mRNA) levels adjusted by serum ferritin values were significantly lower in patients with chronic hepatitis C than in those with chronic hepatitis B or those without hepatitis B virus (HBV) or HCV infection.[38] Of note, the relative expression of hepcidin for iron stores was lower in chronic hepatitis C than in chronic hepatitis B or chronic liver diseases without HBV or HCV infection, even though hepcidin expression levels were strongly correlated with serum ferritin and the degree of hepatic iron deposition. These results suggested that hepcidin might play a pivotal role in iron overload in patients with chronic hepatitis C. A recent study using a validated immunoassay of the 25 amino acid bioactive hepcidin in serum also revealed that serum hepcidin levels were lower in patients with chronic hepatitis C than in controls despite a significant correlation between hepcidin and serum ferritin or the histological iron score in both groups.[39] Thus, the relatively decreased synthesis of hepcidin in chronic hepatitis C contrasts with the absolute deficit or lack in hepcidin synthesis observed in hereditary hemochromatosis and may account for the mild-to-moderate hepatic iron overload observed in some patients with chronic hepatitis C.

Regulation of hepcidin transcription by HCV, iron overload, and inflammation

The next question is how hepcidin transcription is suppressed in the presence of HCV infection. Which pathway for regulating hepcidin transcription is affected? Oxidative stress is present in chronic hepatitis C to a greater degree than in other inflammatory liver diseases.[32] The HCV core protein induces the production of reactive oxygen species (ROS) through inhibition of mitochondrial electron transport.[40] Interestingly, alcohol metabolism-mediated ROS were shown to suppress hepcidin transcription via C/EBPα.[41] Therefore, we investigated the mechanisms underlying hepcidin transcription inhibited by HCV focusing on ROS production, which plays a critical role in the pathogenesis of both alcoholic liver disease and chronic hepatitis C. Hepcidin promoter activity and the DNA binding activity of C/EBPα were downregulated concomitant with increased expression of C/EBP homology protein, an inhibitor of C/EBP DNA binding activity, and with increased levels of ROS in transgenic mice expressing the HCV polyprotein[42] (Fig. 1). Thus, the mechanisms underlying HCV-related hepatic iron overload appear to have some similarities with alcohol-induced iron overload in terms of disrupted hepcidin transcription through suppressed activity of C/EBPα. In agreement with our observation, an in vitro study by Miura et al. using hepatoma cells showed that HCV-induced ROS inhibited the binding activity of C/EBPα to the hepcidin promoter through increased histone deacetylase activity.[43]

jgh12243-fig-0001

Figure 1. Schematic diagram depicting the mechanisms underlying the hepatic iron accumulation in transgenic mice expressing the hepatitis C virus (HCV) polyprotein. HCV protein-induced reactive oxygen species (ROS) increase hepatic expression of CCAAT/enhancer-binding protein (C/EBP) homology protein (CHOP) and subsequently reduce DNA binding activity of C/EBPα, which leads to reduction of hepcidin transcription. Decreased hepcidin expression increases ferroportin (FPN) expression in the enterocytes and reticuloendothelial macrophages resulting in increased duodenal iron transport and macrophage iron release, which lead to hepatic iron accumulation.

Hepcidin is also regulated by both circulating transferrin-bound iron and intracellular iron stores. The exact mechanism is still unknown but seems to involve the BMP/SMAD pathway. As yet, there is no convincing evidence that accounts for the suppressive transcription of hepcidin through the BMP/SMAD cascade in chronic hepatitis C. Taking into account the significant correlation between hepcidin and serum ferritin, or the histological iron score, hepcidin transcription seems to be properly regulated in response to the iron concentration in chronic hepatitis C. Thus, the opposing effects of HCV-induced hepcidin-suppressive factors and iron load-induced hepcidin-stimulation factors potentially regulate hepcidin transcription in chronic hepatitis C. As suggested by Girelli et al.,[39] in the early phase of chronic hepatitis C hepcidin may be prominently suppressed by HCV, but as iron accumulates, the negative influence of viral factors may be masked by the positive stimulation of iron.

Inflammation also regulates hepcidin transcription. Pro-inflammatory cytokines such as IL-6 mediate this response by inducing transcription of hepcidin mRNA via STAT3, which binds to a STAT-responsive element within the hepcidin promoter.[24, 25] Our transgenic mice expressing the HCV polyprotein did not show any inflammation in the liver. A possible pitfall in this experimental model was that we could not take the inflammatory effect on hepcidin regulation into account, which is different from what is observed in patients with chronic hepatitis C. Serum levels of IL-6 have been shown to be elevated in patients with HCV-related chronic liver disease,[44] which raises the possibility that IL-6 acts to stimulate hepcidin expression through the STAT3 pathway. This would be expected to counteract the decrease in hepcidin transcription caused by HCV-induced ROS. However, no significant relationship has been found between serum IL-6 and hepcidin in patients with chronic hepatitis C,[39, 45] even though a paracrine effect of local IL-6 release on hepcidin transcription in the liver cannot be excluded. On the other hand, chronic inflammation with production of pro-inflammatory cytokines has the potential to deliver an additional burden of ROS, which would be expected to reinforce the decrease in hepcidin transcription. Most likely, during chronic inflammation states in vivo like chronic hepatitis C, the regulation of hepcidin is more complex and may depend on many variables, including the particular stage of systemic and/or hepatic inflammatory disease. This might explain the variations in hepatic iron concentrations reported among patients with HCV-related chronic liver disease. The schematic outline in Figure 2 depicts the assumed mechanisms underlying the hepatic iron accumulation in chronic hepatitis C.

jgh12243-fig-0002

Figure 2. Schematic diagram depicting the assumed mechanisms underlying the hepatic iron accumulation in patients with chronic hepatitis C. Hepcidin transcription in chronic hepatitis C may be potentially regulated by the opposing effects of hepatitis C virus (HCV)-related reactive oxygen species (ROS)-induced hepcidin suppression and iron load-induced hepcidin stimulation. Inflammation may also have the opposing effects of stimulation and suppression of hepcidin transcription through the interleukin (IL)-6/signal transducer and activator of transcription (STAT) pathway and ROS pathway, respectively. Consequent relative suppression of hepcidin expression is potentially one of the mechanisms underlying the hepatic iron accumulation in patients with chronic hepatitis C. BMP, bone morphogenetic protein; SMAD, sons of mothers against decapentaplegic.

Relevance of hepatic iron overload to hepatocarcinogenesis

Studies in HCV-infected and uninfected chimpanzees demonstrated that iron loading did exacerbate liver injury in HCV-infected chimpanzees and that HCV infection increased the susceptibility of the liver to injury following iron loading.[46] Increased hepatic iron deposition is reported to be associated with more advanced liver fibrosis in patients with chronic hepatitis C.[47] Recently, it has been prospectively shown in the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis Trial cohort that stainable iron in hepatocytes and portal tract cells predicts progression and outcomes (Child–Pugh score > 7, ascites, encephalopathy, variceal bleeding, spontaneous bacterial peritonitis, HCC, and death) in advanced chronic hepatitis C.[48] Thus, iron is a cofactor that influences the severity and progression of chronic hepatitis C.

Although the association of markedly increased iron accumulation in the liver with hepatocarcinogenesis in hereditary hemochromatosis has been well described,[49] it remains to be elucidated whether mild-to-moderate increases in hepatic iron accumulation contribute to the development of HCC in patients with HCV-associated chronic liver diseases. Nevertheless, there are several lines of evidence that suggest the association of hepatic iron overload with hepatocarcinogenesis in chronic hepatitis C. It has been reported that hepatic iron storage is strongly correlated with hepatic 8-OHdG levels and that subsequent oxidative DNA damage in the liver is associated with an increased risk of HCC development.[2] In addition, the decrease in hepatic 8-OHdG content caused by phlebotomy lowers the risk of progression to HCC, which indeed shows the critical role of the iron-overload state in the development of HCC in patients with chronic hepatitis C.[8, 9]

We investigated whether mild iron overload actually induced HCC in the presence of HCV protein using transgenic mice expressing the HCV polyprotein. Transgenic mice fed an excess-iron diet showed marked hepatic steatosis, including the centrilobular microvesicular type, ultrastructural alterations of the mitochondria and decreased degradation activity of fatty acid at 6 months, as well as hepatic accumulation of lipid peroxidation products and 8-OHdG at 12 months after the initiation of feeding. Of note, hepatic tumors including HCC developed in 5 of 11 (45%) transgenic mice fed the excess-iron diet at 12 months after the initiation of feeding but did not in control mice or transgenic mice fed the control diet.[50] These results indicate the importance of oxidative stress and subsequent mitochondrial injury synergistically induced by iron loading and HCV proteins in the development of HCC. Thus, there seems to be a close relationship between the development of HCC and oxidative DNA damage synergistically induced by hepatic iron accumulation and HCV proteins. However, further investigations are needed to clarify the detailed mechanisms by which hepatic iron accumulation results in the development of HCC in chronic hepatitis C.

Acknowledgments

This research was supported by a Grant-in-Aid for Scientific Research (B) (23390201) from the Japan Society for the Promotion of Science, by a Health and Labor Sciences Research Grant for Research on Hepatitis from the Ministry of Health, Labor and Welfare of Japan and by a Research Project Grant P2 from Kawasaki Medical School.

References

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