AbbVie Amazing All-oral Regimen: 100--96 percent cure rates mostly in 12weeks even in patients w-cirrhosis

In AbbVie's Interferon-free late-stage studies of 6 phase 3 trials most HCV genotype 1 participants achieved an impressive 99% cure rates in 12 weeks. AbbVie said it will file for regulatory approval early in the second quarter, expecting to launch in late 2014. 

AbbVie Completes Largest Phase III Program of an All-Oral, Interferon-Free Therapy for the Treatment of HCV Genotype 1

- Ninety-nine percent SVR(12) rates with and without ribavirin in certain patient types

- Even in difficult-to-treat patients (cirrhotic patients) achieved 92-96 percent SVR(12) rates

- AbbVie expects U.S. launch in 2014

 NORTH CHICAGO, Ill., Jan. 31, 2014 /PRNewswire/ -- AbbVie (NYSE: ABBV) announced the completion of its phase III clinical program and released results of four additional studies designed to assess AbbVie's investigational all-oral, interferon-free therapy with and without ribavirin (RBV) in patients with chronic genotype 1 (GT1) hepatitis C virus (HCV) infection. These results described below confirm previously reported AbbVie data and further demonstrate high sustained virologic response rates 12 weeks post treatment (SVR₁₂) and tolerability in these GT1 patients.

AbbVie Phase III Clinical Program Results 

Study	Patients	Treatment Regimen	SVR12
PEARL-II (12 weeks)	GT1b treatment-experienced (N=179)	AbbVie regimen + RBV (n=88)	97% (85/88)
		AbbVie regimen only (n=91)	100% (91/91)
PEARL-III (12 weeks)	GT1b treatment-naive (N=419)	AbbVie regimen + RBV (n=210)	99% (209/210)
		AbbVie regimen only (n=209)	99% (207/209)
PEARL-IV (12 weeks)	GT1a treatment-naive (N=305)	AbbVie regimen + RBV (n=100)	97% (97/100)
		AbbVie regimen only (n=205)	90% (185/205)
TURQUOISE-II (12 & 24 weeks)	GT1 treatment-naive and treatment-experienced with compensated cirrhosis (N=380)	AbbVie regimen + RBV, 12 weeks (n=208)	92% (191/208)
		AbbVie regimen + RBV, 24 weeks (n=172)	96% (165/172)
SAPPHIRE-I (12 weeks)	GT1 treatment-naive (N=631)	AbbVie regimen + RBV (n=473)	96% (455/473)
SAPPHIRE-II (12 weeks)	GT1 treatment-experienced (N=394)	AbbVie regimen + RBV (n=297)	96% (286/297)

"The outcomes of AbbVie's comprehensive phase III studies in 2,300 patients across 25 countries demonstrate how our investigational regimen performs across a broad spectrum of genotype 1 patients, including those with compensated liver cirrhosis," said Scott Brun, M.D., vice president, pharmaceutical development, AbbVie. "The high rates of response and tolerability of our regimen, coupled with the low rates of discontinuation are promising." 

The AbbVie investigational regimen consists of the fixed-dose combination of ABT-450/ritonavir (150/100mg) co-formulated with ABT-267 (25mg), dosed once daily, and ABT-333 (250mg) with or without ribavirin (weight-based), dosed twice daily. The combination of three different mechanisms of action interrupts the HCV replication process with the goal of optimizing SVR rates across different patient populations. In May of 2013, AbbVie's regimen with and without ribavirin for HCV GT1 was designated as a Breakthrough Therapy by the U.S. Food and Drug Administration (FDA). AbbVie is on track to begin major regulatory submissions early in the second quarter of 2014. AbbVie will disclose detailed study results at future scientific congresses and in publications.

About Study M13-389 (PEARL-II)

 PEARL-II is a global, multi-center, randomized, open-label, controlled study to evaluate the efficacy and safety of 12 weeks of treatment with AbbVie's regimen with and without ribavirin in non-cirrhotic, GT1b HCV-infected, treatment-experienced adult patients.

The study population consisted of 179 GT1b treatment-experienced patients with no evidence of liver cirrhosis: 91 patients randomized to the regimen without ribavirin for 12 weeks, and 88 patients randomized to the regimen with ribavirin for 12 weeks. In the ribavirin-free arm, 100 percent (n=91/91) of patients achieved SVR₁₂, while 97 percent (n=85/88) achieved SVR₁₂ in the ribavirin-containing arm.

The most commonly reported adverse events were fatigue and headache. Discontinuations due to adverse events were reported in none of the patients in the ribavirin-free arm and two (2 percent) patients in the ribavirin-containing arm. There were no patients in either arm of the study that experienced virologic relapse or breakthrough.

About Study M13-961 (PEARL-III)

 PEARL-III is a global, multi-center, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of 12 weeks of treatment with AbbVie's regimen with and without ribavirin in non-cirrhotic, GT1b HCV-infected, treatment-naive adult patients.

The study population consisted of 419 GT1b treatment-naive patients with no evidence of liver cirrhosis: 209 patients randomized to the regimen without ribavirin for 12 weeks, and 210 patients randomized to the regimen with ribavirin for 12 weeks. Following 12 weeks of treatment, 99 percent receiving the regimen without ribavirin (n=207/209) and 99 percent receiving the regimen with ribavirin (n=209/210) achieved SVR₁₂.

The most commonly reported adverse events were headache and fatigue. No patient discontinued study drug due to adverse events. Virologic relapse or breakthrough was noted in none of the patients receiving the regimen without ribavirin and 0.5 percent of patients receiving the regimen with ribavirin.

About Study M14-002 (PEARL-IV)

 PEARL-IV is a global, multi-center, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of 12 weeks of treatment with AbbVie's regimen with and without ribavirin in non-cirrhotic, GT1a HCV-infected, treatment-naive adult patients.

The study population consisted of 305 GT1a treatment-naive patients with no evidence of liver cirrhosis: 205 patients randomized to the regimen without ribavirin for 12 weeks, and 100 patients randomized to the regimen with ribavirin for 12 weeks. Following 12 weeks of treatment, 90 percent of patients receiving the regimen without ribavirin (n=185/205) and 97 percent receiving the regimen with ribavirin (n=97/100) achieved SVR₁₂.

The most commonly reported adverse events were fatigue, headache and nausea. Discontinuations due to adverse events were reported in two (1 percent) patients receiving the regimen without ribavirin and no patients in the ribavirin-containing arm. Virologic relapse or breakthrough was noted in 8 percent of patients receiving the regimen without ribavirin and 2 percent of patients receiving the regimen with ribavirin.

About Study M13-099 (TURQUOISE-II)

 TURQUOISE-II is the first phase III study completed exclusively in GT1 cirrhotic patients investigating an all-oral, interferon-free regimen. It is a global, multi-center, randomized, open-label study evaluating the efficacy and safety of 12 or 24 weeks of treatment with AbbVie's regimen with ribavirin in cirrhotic, GT1a and GT1b HCV-infected, treatment-naive and treatment-experienced adult patients.

The study population consisted of 380 GT1a and GT1b, treatment-naive and treatment-experienced patients with compensated cirrhosis: 208 patients randomized to the regimen with ribavirin for 12 weeks, and 172 patients randomized to the regimen with ribavirin for 24 weeks. Following 12 weeks of treatment, 92 percent of patients (n=191/208) achieved SVR₁₂. Following 24 weeks of treatment, 96 percent of patients (n=165/172) achieved SVR₁₂.

The most commonly reported adverse events were fatigue, headache and nausea. Discontinuations due to adverse events were reported in four (2 percent) patients receiving the regimen with ribavirin for 12 weeks and four (2 percent) patients in the 24-week arm. Virologic relapse or breakthrough was noted in 6 percent of patients in the 12-week arm and 2 percent in the 24-week arm.

Additional information about AbbVie's phase III studies can be found on www.clinicaltrials.gov.

Globally, approximately 160 million people are chronically infected with hepatitis C[1]. AbbVie's multinational HCV program is the largest all-oral, interferon-free clinical program in GT1 patients being conducted to date[2]. GT1 (with subtypes 1a and 1b) is the most prevalent genotype worldwide.

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

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

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

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

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

Ribavirin monotherapy is not effective for the treatment of chronic hepatitis C virus and must not be used alone for this use. Ribavirin causes significant teratogenic effects and must not be used in women who are pregnant or breast-feeding and in men whose female partners are pregnant. Ribavirin must not be used in patients with a history of severe pre-existing cardiac disease, severe hepatic dysfunction or decompensated cirrhosis of the liver, autoimmune hepatitis, hemoglobinopathies, or in combination with peginterferon alfa-2a in HIV/HCV co-infected patients with cirrhosis and Child-Pugh score ≥ 6.

See approved product labels for more information.

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

Forward-Looking Statements

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

Additional information about the economic, competitive, governmental, technological and other factors that may affect AbbVie's operations is set forth in Item 1A, "Risk Factors," in AbbVie's 2012 Annual Report on Form 10-K/A, which has been filed with the Securities and Exchange Commission.

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

[1] Lavanchy D. Evolving epidemiology of hepatitis C virus. Clin Microbiol Infect. 2011; 17(2):107-15.

[2] Comparison based on review of data from www.clinicaltrials.gov for phase 3a programs of Gilead, BMS and BI as of November 15, 2013. 

SOURCE AbbVie

RELATED LINKS
http://www.abbvie.com

Scientists Make New, Less Controversial Type of Stem Cell

 

Published on Jan 30, 2014

View all videos @ GeoBeats News 

Related Article:
Stem cell breakthrough may be simple, fast, cheap
By Elizabeth Landau, CNN

CNN) -- We run too hard, we fall down, we're sick -- all of this puts stress on the cells in our bodies. But in what's being called a breakthrough in regenerative medicine, researchers have found a way to make stem cells by purposely putting mature cells under stress.

Two new studies published Wednesday in the journal Nature describe a method of taking mature cells from mice and turning them into embryonic-like stem cells, which can be coaxed into becoming any other kind of cell possible. One method effectively boils down to this: Put the cells in an acidic environment.

"I think the process we've described mimics Mother Nature," said Dr. Charles Vacanti, director of the laboratory for Tissue Engineering and Regenerative Medicine at Brigham & Women's Hospital in Boston and senior author on one of the studies. "It's a natural process that cells normally respond to."

Both studies represent a new step in the thriving science of stem cell research, which seeks to develop therapies to repair bodily damage and cure disease by being able to insert cells that can grow into whatever tissues or organs are needed. If you take an organ that's functioning at 10% of normal and bring it up to 25% functionality, that could greatly reduce the likelihood of fatality in that particular disease, Vacanti said.........

Continue reading.......

 

Chronic hepatitis B patients with normal alanine transaminase and hepatic fibrosis

Chronic hepatitis B patients with normal alanine transaminase and hepatic fibrosis

February's issue of the Alimentary Pharmacology & Therapeutics investigates the proportion of chronic hepatitis B patients with normal alanine transaminase ≤40 IU/L and significant hepatic fibrosis. 

Volume 39, Issue 4, pages 349–358, February 2014

(Full Text)

Chronic hepatitis B (CHB) may lead to cirrhosis, hepatocellular carcinoma and premature death. Elevated alanine transaminase (ALT) levels ≥ the upper limit of normal (ULN) are a major determinant for initiating anti-viral therapy.

However, ALT levels alone may not be predictive of hepatic fibrosis.
Dr Nguyen and colleagues from California determined the proportion of chronic hepatitis B patients with ALT ≤40 IU/L and liver fibrosis stage ≥2.

Secondary goals include subgroup analysis by hepatitis B e antigen (HBeAg) status, high hepatitis B virus (HBV) DNA levels, Asian ethnicity, lower ULN of ≤30 IU/L (males) and 19 IU/L (females), and advanced age.

Approximately one fifth of patients with ALT ≤40 IU/L may have hepatic fibrosis

Alimentary Pharmacology & Therapeutics

The team identified studies in EMBASE and MEDLINE (1/1990–6/2012) using the search criteria “Hepatitis B”[Mesh] OR “Hepatitis B virus”[Mesh] OR “Hepatitis B, Chronic”[Mesh])) AND “Alanine Transaminase”[Mesh]) and abstracts containing the term ‘hepatitis’ from recent major U.S. gastroenterology and liver society meetings.

Among 9 studies, the team found that a significant proportion of chronic hepatitis B patients with ALT levels ≤40 IU/L had significant fibrosis irrespective of HBeAg status, high HBV DNA levels, ethnicity or age, although this proportion may be higher in patients older than 30–40 years old.

The research team observed that the corresponding proportion was 28% even when the newer ULN of 30 IU/L (males) and 19 IU/L (females) was applied.

Dr Nguyen's team concludes, "Approximately one fifth of chronic hepatitis B patients with ALT ≤40 IU/L may have significant hepatic fibrosis."

"The approach to such patients should be individualized, as further evaluation and treatment may be appropriate."

 Aliment Pharmacol Ther 2014: 39(4): 349–358
30 January 2014

AHF to Ask States to Block Gilead’s $1,000 per Pill Hepatitis Drug From Medicaid Formularies

AHF to Ask States to Block Gilead’s $1,000 per Pill Hepatitis Drug From Medicaid Formularies

Gilead is not the original developer of Sovaldi, its new Hepatitis C medication that will cost $84,000 for a 12-week course of treatment; instead, it bought the drug developer, rival company Pharmasett, for $11 billion cash in 2011. Gilead now seeks a bonanza on a financial investment by gouging cash-strapped government programs, treating states like Gilead’s own private—rigged—stock market.

At $1,000 per pill, Sovaldi price is 1,100% more than Gilead’s AIDS drug combination Stribild ($80 per pill); pharmacy industry sources say Solvaldi’s price suggests a retail markup of 279,000% over production costs.

January 29, 2014 06:53 PM Eastern Standard Time

WASHINGTON--(BUSINESS WIRE)--In a series of letters to be sent to state Medicaid directors starting today, AIDS Healthcare Foundation (AHF) President Michael Weinstein will ask the state directors to block Gilead Sciences’ new $1,000-per-pill Hepatitis C drug Sovaldi (sofosbuvir) from inclusion on their respective state Medicaid and other drug formularies. The drug was approved by the F.D.A. on December 6, 2013 and Gilead immediately announced that it would price the drug at $84,000 for a twelve-week course of treatment—or $1,000 per tablet—making it one of the most expensive drugs ever marketed. Suggested treatment guidelines also require that Sovaldi be used with another drug, ribavirin (a nucleoside inhibitor), further adding to the cost of the prohibitively expensive course of treatment.

“With regard to Sovaldi, it’s time we stopped thinking of Gilead as a drug company and recognize them for what they are here: a pharmaceutical hedge fund bent on exploiting government-funded drug programs like Medicaid and ADAP at the expense of the American taxpayer.”

“When is enough, enough? At $1,000-per-pill, Sovaldi is priced 1,100% more than Gilead’s most expensive AIDS drug, Stribild, its four-in-one AIDS drug combination, which was priced at $80 per pill a year ago when it came to market,” said Michael Weinstein, President of AIDS Healthcare Foundation. “At that time, Stribild’s price was 35% more than Atripla, the company’s best selling combination HIV/AIDS treatment, and made Stribild the highest priced first-line combination AIDS therapy. Now, Gilead has set a new benchmark for unbridled greed with its outrageous price for Sovaldi—a price that some pharmacy industry sources suggest represents a retail markup of 279,000% over the cost of actually producing the drug.”

In his letter to state Medicaid directors, Weinstein wrote, “Gilead is charging a higher price for this drug even though the cost to produce it is small. According to industry reports, Gilead produces Sovaldi for approximately $1.00 per gram (with only 10 to 30 grams needed to successfully treat patients with Hepatitis C).1 This represents a retail markup of over 279,000%. (NOTE: With only 10 to 30 grams of Sovaldi needed for successful treatment, the difference from the $30 production cost for Gilead’s full course of treatment—30 grams x $1.00 per gram—to $84,000 for the 12-week treatment program represents a retail markup of 279,000%.)

Weinstein’s letter to state Medicaid directors also reminds them that, “Gilead did not pay to research and develop Sovaldi. In 2011, it purchased Pharmasset, the company that had already developed the drug, for $11 billion in cash. The pricing of Sovaldi is being driven by Gilead’s desire to recoup its investment in Pharmasset, and assumes it can accomplish this by charging Medicaid and other taxpayer-funded programs whatever it wants.”

“Gilead is now seeking a bonanza on a financial investment—not on its R&D costs of a drug—by gouging cash-strapped government programs, essentially treating states like its own private—rigged—stock market,” added Weinstein. “With regard to Sovaldi, it’s time we stopped thinking of Gilead as a drug company and recognize them for what they are here: a pharmaceutical hedge fund bent on exploiting government-funded drug programs like Medicaid and ADAP at the expense of the American taxpayer.”

AHF’s letter to State Medicaid Directors on Gilead’s Sovaldi:

Re: Formulary Status of Sovaldi and Forthcoming Hepatitis C Medications

AIDS Healthcare Foundation (AHF) is deeply concerned about the fiscal impact of new FDA approved Hepatitis C medications on your Medicaid program, and the effect of that impact on the health care of people in your state. The first of these new medications, Gilead Sciences’ Sovaldi, is exorbitantly priced at $1,000 per pill.

While the approval of Sovaldi and similar treatments is a welcomed advancement for people in need of better treatment for Hepatitis C, the unjustifiably high price manufacturers are seeking to charge for these medications will unnecessarily drive up health care costs and limit access to potentially lifesaving care. Therefore, AHF urgently requests that your Medicaid program deny Sovaldi and other new Hepatitis C medications from being added to your state formulary until these drugs are made affordable.

AHF believes that the price Gilead is charging for Sovaldi is not remotely justified. For one, it is exponentially more expensive than medications for other severe chronic conditions. For example, Gilead’s own Stribild, a costly new four-in-one combo treatment for HIV/AIDS, is $80 per pill. At $1,000 per pill, Sovaldi costs 1,100% more than Stribild, the most-expensive AIDS combo drug on the market.

In addition, Gilead is charging a higher price for this drug even though the cost to produce it is small. According to industry reports, Gilead produces Sovaldi for approximately $1.00 per gram (with only 10 to 30 grams needed to successfully treat patients with Hepatitis C).2 This represents a retail markup of over 279,000%.

Finally, Gilead did not pay to research and develop Sovaldi. In 2011, it purchased Pharmasset, the company that had already developed the drug, for $11 billion in cash. The pricing of Sovaldi is being driven by Gilead’s desire to recoup its investment in Pharmasset, and assumes it can accomplish this by charging Medicaid and other taxpayer-funded programs whatever it wants.

Private drug plans have taken notice of these facts—along with community outrage over the cost of Sovaldi—and have delayed paying for the drug until Gilead agrees to significantly lower the price. For example, Express Scripts, CVS Caremark, Catamaran Inc., and Aetna are all taking steps to block or delay the use of Sovaldi.3 Given this, AHF believes it is imprudent for your state to cover this medication until a better price is available.

Most critically, by taking action to ensure a better price your state will not be putting patient health at risk. There are alternative (and less expensive) treatments for Hepatitis C already available. In addition, Gilead’s patient assistance program provides the treatment for free to people making less than $100,000 a year who cannot access it elsewhere. These steps, while not ideal, will ensure patients continue to receive the care they need until newer medications are made affordable.

Once again, AHF urgently requests you to take action on this matter by denying Sovaldi and other unjustifiably high-priced Hepatitis C medications from your drug formulary until an affordable price is available.

About AIDS Healthcare Foundation

AIDS Healthcare Foundation (AHF), the largest global AIDS organization, currently provides medical care and/or services to more than 279,000 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.

1 NPR,"$1,000 Pill For Hepatitis C Spurs Debate Over Drug Prices.” December 2013. http://www.npr.org/blogs/health/2013/12/30/256885858/-1-000-pill-for-hepatitis-c-spurs-debate-over-drug-prices

2 NPR,"$1,000 Pill For Hepatitis C Spurs Debate Over Drug Prices.” December 2013. http://www.npr.org/blogs/health/2013/12/30/256885858/-1-000-pill-for-hepatitis-c-spurs-debate-over-drug-prices

3 Bloomberg: At $84,000 Gilead Hepatitis C Drug Sets Off Payer Revolt http://www.bloomberg.com/news/2014-01-27/at-84-000-gilead-hepatitis-c-drug-sets-off-payer-revolt.html

Contacts

AIDS Healthcare Foundation
Los Angeles, CA, USA
Ged Kenslea
Communications Director
+1-323-791-5526 [mobile]
+1-323-308-1833 [work]
gedk@aidshealth.org
or
AIDS Healthcare Foundation
Washington, DC, USA
Tim Boyd
Director of Domestic Policy
+1-213-590-7375 [mobile]
timothy.boyd@aidshealth.org

AASLD Launches new online guidance for the treatment of hepatitis C

 Culture Shock: Web-Based Hep C Tx Guidelines

Published: Jan 30, 2014

By Michael Smith, North American Correspondent, MedPage Today

The website was developed and will be run jointly by the American Association for the Study of Liver Diseases, the Infectious Diseases Society of America, and the International Antiviral Society-USA.

A panel of 26 experts will keep clinicians on top of HCV treatment options, spokesmen for the three societies told MedPage Today before the site went live.

He told MedPage Today that the site will contain information -- not only on approved uses, but also on specific off-label drug combinations that have not been through the FDA approval process.
That's because it's not realistic to get specific approval for all possible combinations in all possible patient types, Saag said. A major advantage of the new website, he said, is that the panel can look at all the evidence and "craft [regimens that] experts in the field would be using."

Indeed, the first iteration of the site suggests a combination of two new drugs -- simeprevir (Olysio) and sofosbuvir (Sovaldi) -- that is not specifically approved by the FDA, although both drugs are on the market, according to Donald Jensen, MD, of the University of Chicago Medical Center and a spokesman for the liver society.

Continue reading @ MedPage Today or access the complete report by clicking here. 

AASLD/IDSA Launches up-to-date guidance for the treatment of hepatitis C

Online Expert Advice for Clinicians Treating Hepatitis C Now Available at HCVguidelines.org

Today, the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA), in collaboration with the International Antiviral Society- USA (IAS-USA), announced the launch of a new website, HCVguidelines.org, that will offer up- to-date guidance for the treatment of hepatitis C virus (HCV) infection.

It is estimated that between 3 and 4 million Americans are infected with HCV and have chronic liver disease as a result. The most recent generation of direct-acting antivirals has the potential to cure most patients with HCV. However, the rapid pace of drug development has left medical providers and insurance companies unsure what the optimal treatments are. The guidance provided through HCVguidelines.org will assist clinicians in using these and other treatments in the care of their patients. HCVguidelines.org is the result of an ongoing collaboration between the two medical professional societies and IAS-USA.

New sections will be added, and the recommendations will be updated on a regular basis as new information becomes available. An ongoing summary of "recent changes" will also be available for readers who want to be directed to updates and changes.

The Guidance was developed by a Panel of HCV experts in the fields of hepatology and infectious diseases, using an evidence-based review of information that is largely available to healthcare practitioners, access the complete report by clicking here. 

Full Report Menu
Full Report
INTRODUCTION
METHODS
HCV TESTING AND LINKAGE TO CARE
COMING SOON: In Whom and When to Initiate Treatment
INITIAL TREATMENT OF HCV INFECTION IN PATIENTS STARTING TREATMENT
RETREATMENT OF PERSONS IN WHOM PRIOR THERAPY HAS FAILED
COMING SOON: Monitoring Patients Who Are On or Have Completed Therapy
UNIQUE PATIENT POPULATIONS
COMING SOON: Management of Acute HCV Infection
REFERENCES
WEBSITE POLICIES

Boehringer Ingelheim halts further development of deleobuvir-containing hepatitis C regimens

Boehringer Ingelheim halts further development of deleobuvir-containing hepatitis C regimens

January 17, 2014 Reprinted from company statement by Boehringer Ingelheim

Following an assessment of the blinded Phase 3 trial data from HCVerso® 1 and 2 for the combination of deleobuvir, faldaprevir and ribavirin, Boehringer Ingelheim has decided to halt further development of deleobuvir-containing hepatitis C (HCV) regimens.

The combination showed a higher rate of premature discontinuations suggesting a lower efficacy rate compared to other interferon-free therapies in development. Boehringer Ingelheim has therefore concluded that the expected therapeutic value of the deleobuvir-containing regimen would not justify further development.

Faldaprevir, Boehringer Ingelheim's investigational HCV protease inhibitor, has shown promising results in combination with pegylated interferon and ribavirin in the STARTVerso™ trials. Ongoing regulatory reviews of faldaprevir are not affected by the decision on the deleobuvir-containing regimens. In the US, Boehringer Ingelheim will move forward with the submission process for faldaprevir.

Boehringer Ingelheim is committed to developing new treatments that provide high therapeutic value in areas of unresolved medical need. The company is focusing its efforts on numerous promising development projects in areas, such as immunology, cardiovascular, respiratory, metabolic diseases, diseases of the central nervous system and oncology.
 
Related:
Published Aug 2013 in the New England Journal of Medicine: Faldaprevir and Deleobuvir for HCV Genotype 1 Infection

November 2013
Hepatitis C: Boehringer Ingelheim’s faldaprevir granted accelerated assessment from European Medicines Agency

Singapore scientists make pure precursor liver and pancreas cells from stem cells

28 January 2014

Singapore scientists succeed in manipulating stem cells into liver and pancreas precursor cells 

Scientists from the Genome Institute of Singapore (GIS) in A*STAR have developed a novel method of directing human pluripotent stem cells (hPSCs) into highly pure populations of endoderm[1], a valuable cell type that gives rise to organs including the liver and pancreas.

These cells are highly sought-after for therapeutic and biotechnological purposes, but have been historically difficult to attain from hPSCs. The ability to generate pure endoderm at higher yields from hPSCs is a key and important step towards the use of stem cells in clinical applications.

The discovery, published in the prestigious scientific journal Cell Stem Cell in January 2014, was led by Dr Bing Lim, Senior Group Leader and Associate Director of Cancer Stem Cell Biology at the GIS, Dr Lay Teng Ang, a postdoctoral fellow from Dr Lim’s lab, and Kyle Loh, a graduate student at Stanford University School of Medicine. 

hPSCs are stem cells that can generate over 200 distinct cell types in the human body. They respond to multiple external protein instructions to differentiate into other cell types. Therefore, generating one single cell type from hPSCs, and a pure population of that given cell type, is delicate as hPSCs have a tendency to also form other types of cells.

Employing a highly systematic and novel approach, the group screened for proteins and chemicals that promote the formation of a single desired cell type, and concurrently block induction of unwanted cell types. This strategy uncovered a combination of triggers that could drive hPSCs towards pure populations of endoderm. The valuable cells produced and the insights gained from this work have brought stem cells one step closer to clinical translation and furthered basic research into the understanding of how cell fates are specified during stem cell differentiation.

Prof Thomas Graf, Coordinator of the Differentiation and Cancer Programme at the Center for Genomic Regulation, Barcelona, commented, “Using this novel strategy, the work beautifully shows how hPSCs can be guided to differentiate into the endoderm cells at high efficiencies. The strategy described should be more widely applicable to other desired cell types.”

Next, leveraging the highly pure population of endoderm cells, the team utilised GIS’ expertise in next-generation sequencing as well as bioinformatics and accurately characterised the transcriptional and enhancer states of these highly pure cells. Enhancers are DNA elements that can become activated to increase the expression of flanking genes. In hPSCs, a category of dormant enhancers was reported to be pre-configured before subsequently becoming activated when the cells differentiate.

Dr Shyam Prabhakar, Group Leader of Computational and Systems Biology, and Associate Director of Integrative Genomics at the GIS said, “Our new results indicate that the reality is more complex. Beyond current scientific knowledge, we found a larger superset of inactive enhancer states, all of which have the ability to convert to an active state upon cell differentiation.”

The study not only provides a more comprehensive model of enhancer regulation of cellular differentiation, it also provides a valuable resource for the scientific community. Prof Ken Zaret of the Department of Cell and Developmental Biology at the University of Pennsylvania said, “The rich trove of genomic data from their hESC work beautifully illustrates the power of having developed a rigorous developmental system that will serve as a resource for years to come”.

Dr Lim added, “This unprecedented access to highly pure population of endodermal cells attracts pharmaceutical companies, who are interested in further making human liver cells to tests drug toxicities.”

GIS’ Executive Director Prof Ng Huck Hui said, "This is a beautiful piece of work to delineate the early events in cell fate decision. The findings will enable researchers to obtain high quality endodermal cells for future applications."

The study was done in collaboration with the Stanford University School of Medicine, the Stanford Institute for Stem Cell Biology & Regenerative Medicine, the Computational and Systems Biology group at the GIS, A*STAR’s Institute of Molecular and Cell Biology, the Murdoch Children’s Research Institute and Monash University, the Temasek Polytechnic, and the Cancer Science Institute of Singapore.

­­­­­

The research findings described in the press release have been published as an advanced online publication in Cell Stem Cell on 9 January, 2014 under the title “Efficient Endoderm Induction from Human Pluripotent Stem Cells by Logically Directing Signals Controlling Lineage Bifurcations”.

Authors:

Kyle M. Loh,^1,2,11,* Lay Teng Ang,^1,11,* Jingyao Zhang,^1,12 Vibhor Kumar,^1,12 Jasmin Ang,¹ Jun Qiang Auyeong,¹ Kian Leong Lee,³ Siew Hua Choo,¹ Christina Y.Y. Lim,¹ Massimo Nichane,¹ Junru Tan,¹ Monireh Soroush Noghabi,¹ Lisa Azzola,⁴ Elizabeth S. Ng,^4,5 Jens Durruthy-Durruthy,² Vittorio Sebastiano,² Lorenz Poellinger,³ Andrew G. Elefanty,^4,5 Edouard G. Stanley,^4,5 Qingfeng Chen,^6,7,8 Shyam Prabhakar,¹ Irving L. Weissman,² and Bing Lim^1,9,10,*

1.    Stem Cell and Developmental Biology Group, Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore 138672, Singapore

2.    Department of Developmental Biology, Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA

3.    Cancer Science Institute of Singapore, Centre for Translational Medicine, National University of Singapore, Singapore 117599, Singapore

4.    Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC 3800, Australia

5.    Murdoch Childrens Research Institute, The Royal Children’s Hospital, Parkville, VIC 3052, Australia

6.    Humanized Mouse Unit, Institute of Molecular and Cell Biology, A*STAR, Singapore 138673, Singapore

7.    Interdisciplinary Research Group in Infectious Diseases, Singapore-MIT Alliance for Research and Technology, Singapore 138602, Singapore

8.    Department of Microbiology, Yong Yoo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore

9.    Department of Medicine, Harvard Medical School, Boston, MA 02115, USA

10.  Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA

11.  These authors contributed equally to this work

12.  These authors contributed equally to this work

Celsion plans new late-stage trial of liver cancer drug ThermoDox based on data from study

Celsion plans new study of liver cancer drug

Celsion plans new late-stage trial of liver cancer drug ThermoDox based on data from study

Related Jan 2013 - Liver Cancer-Phase III HEAT trial of Thermodox Fails to Meet Goals

NEW YORK (AP) -- Celsion said Monday it wants to start another late-stage clinical trial of its liver cancer drug ThermoDox. 

The company said a year ago that ThermoDox did not meet its main goal in a clinical trial because it didn't improve their time to death or disease progression. Celsion said it is still following patients from that trial and said some may be living longer.

ThermoDox is heat-activated and is designed to deliver bigger doses of the chemotherapy drug doxorubicin directly to tumors. The trial compared a combination of ThermoDox and radiofrequency ablation, a treatment that uses heat to destroy unhealthy tissue, to radiofrequency ablation alone. Celsion said Monday that patients who received ThermoDox and at least 45 minutes of radiofrequency ablation appeared to live longer.

The Lawrenceville, N.J., company said it has been consulting with regulators and wants to start a new late-stage trial in the first half of 2014.

Read more...


January 27, 2014- Press release:
Celsion Corporation Announces Updated Overall Survival Results from Phase III HEAT Study of ThermoDox® in Primary Liver Cancer

Latest Data from Large Subgroup of Patients Shows that the Combination of ThermoDox® and Optimized RFA Provides a Statistically Significant Survival Improvement of Over 50%
Provides Basis for Further Development of ThermoDox® in HCC Patients

LAWRENCEVILLE, N.J., Jan. 27, 2014 /PRNewswire/ -- Celsion Corporation (NASDAQ: CLSN) today announced that the latest overall survival data from its post-hoc analysis of results from the Company's Phase III HEAT Study of ThermoDox®, Celsion's proprietary heat-activated liposomal encapsulation of doxorubicin in combination with radio frequency ablation (RFA), supports the continued clinical development of ThermoDox® in a prospective pivotal Phase III Study, subject to regulatory review and agreement. This analysis followed the announcement on January 31, 2013, that the HEAT Study did not meet its primary endpoint, progression-free survival (PFS). As provided for in the HEAT Study's Special Protocol Assessment (SPA) agreement with the U.S. Food and Drug Administration (FDA), the Company continues to follow patients for overall survival, the secondary endpoint of the Study. Data from four quarterly reviews of overall survival have been evaluated since the announcement of top line PFS data.

Data from the updated HEAT Study analysis suggests that ThermoDox® may significantly improve overall survival, compared to control, in patients whose lesions undergo RFA treatment for 45 minutes or more. These findings apply to patients with single HCC lesions (64.4% of the HEAT Study population) from both size cohorts of the HEAT Study (3-5 cm and 5-7 cm) and represent a subgroup of 285 patients (41% of the patients in the HEAT Study). Updated OS data from this subgroup of patients is summarized below:

In the patient subgroup treated in the ThermoDox® arm, whose RFA procedure lasted longer than 45 minutes (285 patients or 63% of single lesion patients) clinical results indicate a 55% improvement in overall survival, a Hazard Ratio of 0.64 (95% CI 0.41 - 1.00) and a P-value = 0.0495. Median overall survival for this subgroup has not yet been reached.

In contrast, the patient subgroup treated with ThermoDox® whose RFA procedure lasted less than 45 minutes in duration (167 patients or 37% of single lesion patients) indicated a Hazard Ratio of 1.12 (95% CI 0.68 - 1.86) and a P-value = 0.66. Median overall survival for this subgroup has not yet been reached.

The Hazard Ratios reported above warrants additional clinical development and should be viewed with caution since they are based on a retrospective analysis and the HEAT Study has not reached its median point for overall survival analysis. Celsion will continue to follow patients in the HEAT Study to the secondary endpoint, overall survival, and will update the subgroup analysis based on RFA heating duration.

"The HEAT Study post-hoc data is compelling. The combination of ThermoDox® and an optimized RFA treatment appears to have a significant improvement in overall survival in HCC patients," stated Dr. Nicholas Borys, Celsion's Chief Medical Officer. "While this conclusion is reached based on a post-hoc evaluation, it is nonetheless supported by the consistency of the data seen over a one year follow-up period, and by what is now a statistically significant outcome for overall survival. Our investigators are convinced that RFA can and should be optimized in future trials."

The HEAT Study and prior post-hoc analyses were presented at three medical conferences in 2013, including the World Conference on Interventional Oncology in May; the European Conference on Interventional Oncology in June and the International Liver Cancer Association Annual Conference in September. Presentations were made by some of the most highly recognized liver cancer researchers and key HEAT Study investigators. Quarterly overall survival data analyses have been conducted with the full support of these researchers and clinical investigators.

Additionally, Celsion has been consulting with its clinical advisors, regulatory and expert statistician consultants and the FDA regarding the study design and statistical plan for its proposed pivotal Phase III clinical trial. The Company anticipates initiating a multicenter global trial in the first half of 2014.

"These data continue to support our strong interest in ThermoDox® and its potential as a first line treatment for a significant percentage of the world's 750,000 newly diagnosed HCC patients," noted Michael H. Tardugno, Celsion's President and Chief Executive Officer. "In addition to the FDA, the Company is pursuing regulatory approval of its new Phase III clinical trial in multiple countries, particularly those where HCC's prevalence represents an important health issue. In parallel with this effort, we are recruiting key CRO partners to initiate the Study rapidly following regulatory agency agreement. With our strong financial resources and the support of the global HCC community, we are confident in our ability to conduct a timely and cash efficient pivotal program."

About Celsion Corporation
Celsion is dedicated to the development and commercialization of innovative cancer drugs, including tumor-targeting treatments using focused heat energy in combination with heat-activated liposomal drug technology. Celsion has research, license or commercialization agreements with leading institutions, including the National Institutes of Health, Duke University Medical Center, University of Hong Kong, the University of Pisa, the UCLA Department of Medicine, the Kyungpook National University Hospital, the Beijing Cancer Hospital and the University of Oxford. For more information on Celsion , visit our website: http://www.celsion.com.

Celsion wishes to inform readers that forward-looking statements in this release are made pursuant to the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995. Readers are cautioned that such forward-looking statements involve risks and uncertainties including, without limitation, unforeseen changes in the course of research and development activities and in clinical trials; the uncertainties of and difficulties in analyzing interim clinical data, particularly in small subgroups that are not statistically significant; FDA and regulatory uncertainties and risks; the significant expense, time, and risk of failure of conducting clinical trials; HEAT Study data is subject to further verification and review by the HEAT Study Data Management Committee; the need for Celsion to evaluate its future development plans; possible acquisitions or licenses of other technologies, assets or businesses or the possible failure to make such acquisitions or licenses; possible actions by customers, suppliers, competitors, regulatory authorities; and other risks detailed from time to time in the Celsion's periodic reports and prospectuses filed with the Securities and Exchange Commission. Celsion assumes no obligation to update or supplement forward-looking statements that become untrue because of subsequent events, new information or otherwise.

Investor Contact
Jeffrey W. Church
Senior Vice President and
Chief Financial Officer
609-482-2455
jchurch@celsion.com

SOURCE Celsion Corporation

News Provided by Acquire Media
http://investor.celsion.com/releasedetail.cfm?ReleaseID=821197

Video Dr. Galati: Basics Of Encephalopathy-A Serious Complication Of Cirrhosis

See all videos - Joe Galati, M.D.
Website

Jan 28
Video: Hepatic encephalopathy
Hepatic encephalopathy is a serious complication of cirrhosis and portal hypertension. Dr. Joseph Galati, with Houston Methodist, explains the basics of hepatic encephalopathy, and reviews risk factors and treatment options. Patients that develop hepatic encephalopathy in many cases require consideration for liver transplant. Once hepatic encephalopathy develops, it is generally a signal that the liver is in the advancing stages of damage, and there is a decreased survival associated with it. There are medications available to treat hepatic encephalopathy.

Symptoms of hepatic encephalopathy include fatigue, difficulty sleeping, excessive sleep, memory loss, changes in behavior and personality, confusion, and possible coma.

Hepatitis C and Cirrhosis-A New Laboratory Based Algorithm to Predict Development of Hepatocellular Carcinoma

Gastroenterology. 2014 Jan 23. pii: S0016-5085(14)00104-8. doi: 10.1053/j.gastro.2014.01.045.

PDF 

A New Laboratory Based Algorithm to Predict Development of Hepatocellular Carcinoma in Patients with Hepatitis C and Cirrhosis.

El-Serag HB1, Kanwal F2, Davila JA3, Kramer J4, Richardson P5.

1Houston VA HSR&D Center of Excellence. Electronic address: hasheme@bcm.edu.
2Section of Health Services Research.
3Gastroenterology and Hepatology, Michael E. DeBakey VA Medical Center.
4Baylor College of Medicine, Houston, Texas.
5Houston VA HSR&D Center of Excellence.

Abstract
BACKGROUND & AIMS:
Serum levels of α-fetoprotein (AFP) are influenced not only by the presence of hepatocellular carcinoma (HCC) but also by underlying severity and activity of liver disease, which is reflected by liver function tests. We constructed an AFP-based algorithm that included these factors to identify patients at risk for HCC, and tested its predictive ability in a large set of patients with cirrhosis.

METHODS:
We used the national Veterans Administration hepatitis C virus (HCV) clinical case registry to identify patients with cirrhosis, results from at least 1 AFP test, and 6 months of follow up. Our algorithm included data on age; levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, total bilirubin, albumin, creatinine, and hemoglobin; prothrombin time; and numbers of platelets and white cells. We examined the operating characteristics (calibration, discrimination, predictive values) of several different algorithms for identification of patients who would develop HCC within 6 months of the AFP test. We assessed our final model in the development and validation subsets.

RESULTS:
We identified 11,721 patients with HCV-related cirrhosis in whom 35,494 AFP tests were performed, and 987 patients developed HCC. A predictive model that included data on levels of AFP, ALT, and platelets, along with age at time of AFP test (and interaction terms between AFP and ALT, and AFP and platelets), best discriminated between patients who did and did not develop HCC. Using this AFP-adjusted model, the predictive accuracy increased at different AFP cutoffs, compared with AFP alone. At any given AFP value, low numbers of platelets and ALT and older age were associated with increased risk of HCC, whereas high levels of ALT and normal/high numbers of platelets were associated with low risk for HCC. For example, the probabilities of HCC, based only on 20 ng/ml and 120 ng/ml AFP, were 3.5% and 11.4%, respectively. However patients with the same AFP values (20 ng/ml and 120 ng/ml) who were 70 y old, with ALT levels of 40 IU/ml and platelet counts of 100,000, had probabilities of developing HCC of 8.1% and 29.0%, respectively.

CONCLUSIONS:
We developed and validated an algorithm based on levels of AFP, platelets, and ALT, along with age, which increased the predictive value for identifying patients with HCV-associated cirrhosis likely to develop HCC within 6 months. If validated in other patient groups, this model would have immediate clinical applicability.

Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.

KEYWORDS:
liver cancer, prediction, prognosis, risk factors

Gilead - Paul Carter and John McHutchison, MD Named Executive Vice Presidents

-- Robin Washington, Paul Carter and John McHutchison, MD Named Executive Vice Presidents --

FOSTER CITY, Calif.--(BUSINESS WIRE)--Jan. 27, 2014-- Gilead Sciences, Inc. (Nasdaq: GILD) today announced several promotions within the company's senior management team. Robin Washington, Chief Financial Officer (CFO), has been promoted to Executive Vice President; Paul Carter, formerly Senior Vice President, International Commercial Operations, has been promoted to Executive Vice President with responsibility for Gilead's worldwide commercial organization; and John McHutchison, MD, formerly Senior Vice President, Liver Disease Therapeutics, has been promoted to Executive Vice President and will assume additional responsibility for clinical development programs in the areas of oncology, respiratory diseases and inflammation.

"Robin, Paul and John have made significant contributions to Gilead, each demonstrating a commitment to improving systems and processes and advancing programs that will allow us to meet the needs of patients as quickly as possible," commented John C. Martin, PhD, Chairman and Chief Executive Officer, Gilead Sciences. "They have each built strong, capable teams and have helped Gilead navigate an increasingly complex environment as we expand geographically and into new therapeutic categories. Their leadership and vision will help ensure Gilead is able to achieve our goals and reach more patients in need around the world."

Ms. Washington joined Gilead in 2008 as Senior Vice President and CFO. She oversees the company's finance, information technology and investor relations functions, reporting to John Milligan, PhD, Gilead's President and Chief Operating Officer. Prior to joining Gilead, Ms. Washington was Chief Financial Officer of Hyperion Solutions, which was acquired by Oracle Corporation in March 2007. She previously served in a number of executive positions with PeopleSoft, most recently in the role of Senior Vice President and Corporate Controller. Ms. Washington is a member of the Board of Directors of Honeywell International, the Board of Directors of Salesforce.com and the Board of Visitors, Graziadio School of Business and Management, Pepperdine University. She is a certified public accountant and holds a bachelor's degree in business administration from the University of Michigan and an MBA from Pepperdine University.

Mr. Carter joined Gilead Sciences in April 2006 to head its European commercial organization. Later that year he assumed additional responsibility for Gilead's growing operations outside of Europe and North America. He has helped to establish the company's regional Asian headquarters in Hong Kong and numerous new affiliate offices, most recently including operations in the Czech Republic, Poland, Russia and South Korea. In his new role, Mr. Carter will oversee worldwide commercial operations, reporting to Dr. Milligan. Prior to joining Gilead, Mr. Carter spent 15 years in the pharmaceutical industry with GlaxoSmithKline and its legacy companies. During his time with GSK, Mr. Carter gained increasing levels of senior experience as General Manager in Europe and later as a Regional Head of the International business in Asia. In this latter role he was also a member of GSK's International Management Committee. Mr. Carter's early experience includes several years with Arthur Andersen at its London office. He has a degree in Business Studies from the Ealing School of Business and Management (now merged into University of West London) and is a Fellow of the United Kingdom's Chartered Institute of Management Accountants.

Dr. McHutchison joined Gilead in 2010 as Senior Vice President, Liver Disease Therapeutics. In his newly expanded role, he will be responsible for Gilead's development programs in oncology, respiratory diseases and inflammation. Dr. McHutchison will continue to report to Norbert Bischofberger, PhD, Executive Vice President, Research and Development and Chief Scientific Officer. Prior to joining Gilead, Dr. McHutchison worked at Duke University Medical Center, where he served as Associate Director of the Duke Clinical Research Institute. He also held the positions of Professor of Medicine in the Division of Gastroenterology at Duke University Medical Center and Co-Director of the Duke Clinical and Translational Science Award. Prior to his positions at Duke, Dr. McHutchison spent nearly 10 years at Scripps Clinic, most recently as Medical Director, Liver Transplantation. He also previously held an Assistant Professorship in Medicine at the University of Southern California. Dr. McHutchison received bachelor of medicine and bachelor of surgery degrees from the University of Melbourne, Australia, and completed his residency in internal medicine and a fellowship in gastroenterology at the Royal Melbourne Hospital. He is also a member of the Royal Australasian College of Physicians.

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. 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.

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.

At $84,000 Gilead Hepatitis C Drug Sets Off Payer Revolt

At $84,000 Gilead Hepatitis C Drug Sets Off Payer Revolt

By Drew Armstrong

As Gilead Sciences Inc. (GILD) touted its $1,000-a-pill hepatitis C cure to investors in a hotel ballroom in San Francisco last week, a group of about 20 protesters milled outside. “Gilead=Greed,” one sign read.

“I’m glad people have the new drugs, but I’m concerned about the prices,” said Orlando Chavez, 62, a hepatitis C and HIV counselor and one of the protesters. He worries that insurers will see Gilead’s price and force patients to try a less effective, older and cheaper therapy first, he said.

Chavez has good reason to worry.

Payers face billions of dollars in new drug costs as pharmaceutical companies develop increasingly complex products in the years ahead. Express Scripts Holding Co. (ESRX), Catamaran Corp. (CCT), Aetna Inc. and CVS Caremark Corp. (CVS) among others are already pushing back against the high cost of Gilead’s drug. They’re discussing how to pit similar drugs against each other, refusing coverage for some, or subjecting treatments to more review by outside experts and refusing to pay a premium based on one drug being more convenient to take than another.

Gilead’s new drug, Sovaldi, costs $84,000 for a 12-week treatment. Such breakthrough treatments and their stratospheric price tags have “absolutely” caused insurers to reconsider covering high-priced hepatitis, diabetes and other treatments, said Sumit Dutta, chief medical officer of Catamaran, the fourth-biggest U.S. pharmacy benefit manager, or PBM.

“You can’t manage exclusively by the techniques PBMs have used in the past,” Dutta said by telephone. “We’re seeing the shift, where payers are finally going to say, ’It’s $84,000, and the other therapy is $50,000 -- what am I getting?’”
Stock Valuation

For drugmakers and biotechnology companies that have zeroed in on high-priced treatments to replace blockbusters such as Lipitor, the Pfizer Inc. cholesterol drug that once drew more than $12 billion a year before losing ground to generics, the change may affect how shareholders value their stocks, according to Les Funtleyder, a health industry expert and author of the book “Health-Care Investing.”

“There’s been a feeling among investors that biotech drugs are immune from price competition,” Funtleyder said in an interview. “We’re getting to where we may have may reached a pain point.”

Prescription drugs make up an increasing share of U.S. health care spending. Spending on hepatitis C drugs alone is projected to rise seven-fold from $3 billion a year in 2011 to $21 billion in 2018, according to market research firm Decision Resources Group LLC. U.S. drug spending will grow 6.5 percent a year from 2015 to 2022, faster than overall health costs, according to the U.S. Centers for Medicare and Medicaid Services. That’s mostly driven by rising prices and a leveling off of generic drug use, according to the U.S. report.

Cost Debate

It will take Gilead three to six months since it was approved Dec. 6 to formalize coverage with payers and PBMs, said Chief Operating Officer John Milligan in an e-mail. In the meantime, most plans are covering it, he said.

When eventually combined with a second drug Gilead is studying, the regimen’s price could rise to $100,000 or more per year, compared to what Catamaran says is about $66,000 for the current standard of care.

That’s still cheaper than treating complications of hepatitis C, which can lead to liver damage or failure and the eventual need for transplant, said Gilead’s Milligan.

“In our conversations with payers, pricing is a consideration, but efficacy, safety and treatment guidelines are equally important,” Milligan said.

Tools Available

Besides payers already have plenty of tools to push back on costs and force patients to try cheaper medicines first, and they use them, said the drug industry’s Washington trade group, Pharmaceutical Researchers and Manufacturers of America. “Typically by the time the patients get through the various steps they need to get to the product, they really do need it,” said Lori Reilly, PhRMA’s head of policy.

Even so, payers are thinking twice before opening their wallets. Jeff Park, Catamaran’s chief financial officer, said some prescription plans managed by his company are already pushing patients to try older therapies first, moving to the more expensive ones only and only if they fail.

“You can get to these more expensive treatments,” Park said in an interview in San Francisco during the JPMorgan Chase& Co. health-care conference. But to do so, “you have to outweigh the costs of the first, more cost-effective treatment.”

That’s a big concern for patients and advocates such as Chavez who say that strategy will force them to stick with side-effect-heavy older hepatitis C treatments that rely on difficult weekly injections, making a patient feel as if they have the flu over and over again.

Brutal Regimen

Chavez contracted hepatitis C before the latest treatments were available. Now recovered, he helps others get hepatitis C as well as HIV treatment in the San Francisco Bay area. He took injections of interferon, an older drug, for almost a year to rid his body of the virus. It was a brutal regimen, he said, though it worked.

“It was terrible,” Chavez said. “I was up against it, so I had to do it, But if I had the choice today I wouldn’t.”

He and others may not have that choice.

Last year, Express Scripts stopped covering insulins and a diabetes injection made by Novo Nordisk A/S in favor of products from Eli Lilly & Co., AstraZeneca Plc and Bristol-Myers Squibb Co. (BMY) In the last four weeks, prescriptions of Lilly’s insulin Humalog are up 15 percent compared with the four weeks before Express Scripts’ change, while prescriptions of Novo’s Novolog are flat.

Comparing Drugs

Express Scripts and other pharmacy managers have since said that they’re ready to block other drugs from coverage.

“We will identify which drugs can be pitted against each other and make some really tough formulary decisions,” the company’s Chief Medical Officer Steven Miller said in a December interview.

In the U.K. and Europe, health regulators regularly weigh the benefit of drugs against their cost when deciding what the countries’ national health systems will pay for. Bristol-Myers stopped selling a diabetes drug in Germany last month after the government refused to meet its price, for example.

Obamacare Customer

Obamacare could have a similar effect as individuals begin to weigh the cost of insurance products, said Jami Rubin, an analyst with Goldman Sachs Group Inc. With the Affordable Care Act’s insurance expansion, millions of new customers in the law’s health care marketplaces will be picking and choosing among drug plans based on cost and coverage, instead of having their company pick a plan for them.

“What will society pay for a cure?,” said Rubin. “Is a cure worth $1,000 a day?”

To contact the reporter on this story: Drew Armstrong in New York at darmstrong17@bloomberg.net

To contact the editor responsible for this story: Reg Gale at rgale5@bloomberg.net

Source - Bloomberg 

Related @ Fierce Pharma
Spurred by pricey Gilead hep C drug, payers cook up new cost-control moves
Pharmacy benefits managers - PBMs might refuse to pay a higher price for drugs that are more convenient to take than cheaper alternatives are. They might not cover all new drugs in a new generation of treatments, opting to analyze the field and choose the best--and most cost-effective--option. They might even bring in outside experts to review the data, just as cost-effectiveness watchdogs in other countries do.

Management of Chronic Hepatitis C in Patients With Contraindications to Anti-viral Therapy

Alimentary Pharmacology & Therapeutics

Review Article
Management of Chronic Hepatitis C in Patients With Contraindications to Anti-viral Therapy
V. CarreñoDisclosures

Aliment Pharmacol Ther. 2014;39(2):148-162.

Abstract and Introduction
Abstract 

Background There are patients with chronic hepatitis C who are not eligible for the current interferon-based therapies or refuse to be treated due to secondary effects.
Aim To provide information on alternative treatments for the management of these patients.
Methods A PubMed search was performed to identify relevant literature. Search terms included hepatitis C virus, anti-inflammatory treatment, antioxidant, natural products and alternative treatment, alone or in combination. Additional publications were identified using the references cited by primary and review articles.
Results Several approaches, such as iron depletion (phlebotomy), treatment with ursodeoxycholic acid or glycyrrhizin, have anti-inflammatory and/or anti-fibrotic effects. Life interventions like weight loss, exercise and coffee consumption are associated with a biochemical improvement. Other alternatives (ribavirin monotherapy, amantadine, silibinin, vitamin supplementation, etc.) do not have any beneficial effect or need to be tested in larger clinical studies.
Conclusion There are therapeutic strategies and lifestyle interventions that can be used to improve liver damage in patients with chronic hepatitis C who cannot receive or refuse interferon-based treatments.

Introduction
Treatment of chronic hepatitis C virus (HCV) is aimed to eradicate HCV and to prevent liver disease progression. All currently approved anti-viral therapies against HCV are pegylated-interferon (PEG-IFN)-based. Response rates in patients with genotype 1 have increased with the implementation of the triple therapy of PEG-IFN plus ribavirin (RBV) plus protease inhibitors. However, around 25% of naïve patients with HCV genotype 1 infection and about 70% of null responders to previous anti-viral treatment do not respond to triple therapy.^[1] In addition, there are patients in whom current therapies are contraindicated (low platelet count, advanced liver disease, coronary artery disease, autoimmunity, seizure disorders, pregnancy), or who are intolerant to IFN-based therapies or who refuse to be treated due to the side effects.^[2,3] IFN-free regimens are near approval for many patients but, while awaiting these new therapies, measures to slow liver disease progression (that could make future therapy difficult and less beneficial) should be adopted. Furthermore, there will be still some patients who could not be treated with these upcoming therapies. In the present review, other options for the treatment and clinical management of chronic hepatitis C are summarised.

Iron Depletion and Drug Interventions
Phlebotomy
Iron overload is a common finding in patients with chronic hepatitis C and elevated iron indices are correlated with the progression of liver disease.^[4,5] An excess of iron induces formation of reactive oxygen species that activate hepatic stellate cells, which contribute to hepatic fibrogenesis.^[6] Iron depletion via phlebotomy has been used as a collateral treatment of chronic hepatitis C. In the first report by Bacon et al.,^[7] eight patients who failed to respond to IFN were treated by weekly phlebotomy (500 mL) until iron deficiency was achieved (after 5–10 units of blood were removed). After phlebotomy, serum alanine amino transferase (ALT) fell in all but one patient, but serum HCV-RNA levels did not change. Following this report, several studies on iron depletion by phlebotomy in these patients have been published and the finding of that first report was confirmed.^[8–16]

Generally, phlebotomies (between 200 and 400 mL) have been applied in different studies (Table 1) with a weekly or monthly frequency to reach a decrease in ferritin up to 10 ng/mL,^[8,9,20] although in some studies the limit of reduction was 50–60 ng/mL.^[10,11] The limit of reduction in haemoglobin was 11 g/dL.^[13] In these studies, patients underwent repeated phlebotomies to maintain the iron deficiency state. Usually, the total amount of blood removed to achieve an iron deficiency state oscillated between 2.5 and 3.5 L and men needed around 0.5 L more blood removed than women.^{[8–11,14,17,18,21]} In all these studies, a significant reduction in ALT and ferritin levels (the majority of the included patients had increased basal values of ferritin) was achieved. Time required to obtain this iron depletion was 5 ± 2 months.^[9] The percentage of ALT normalisation oscillated between 10% and 69%.^[8,18] This percentage of normalisation increased with prolongation of therapy to maintain iron deficiency over time. These studies included patients who were nonresponders to anti-viral therapy or naïve patients with a similar response between them.^[8–10,18] Serum HCV-RNA levels did not change during or after treatment. No important secondary effects were observed during treatment. It has been reported ascitis development has been reported in two patients treated with phlebotomy who had a serum albumin <3.6 g/dL. Hence, in these type of patients, phlebotomy should be used with caution.^[17]
 
The effect of phlebotomy on the liver histology of patients with chronic hepatitis C has been demonstrated in several reports. Thus, Yano et al.^[20] treated 25 patients with maintained phlebotomies (5 years) and included a control group (n = 13) who were nonresponders to interferon. A second liver biopsy was obtained more than 3 years after the beginning of phlebotomies. They observed a significant reduction in the fibrosis score from 2.3 to 1.7 in the phlebotomy group, while this score increased from 1.7 to 2.0 in the controls. Moreover, the severity of inflammation increased significantly in the control group (from 2.0 to 2.9), but remained unchanged in the phlebotomy group. Similar results were obtained by other authors.^[19,22] A high hepatic iron concentration before treatment has been reported associated with histological improvement.^[19] Thus, up to 70% of patients with hepatic iron concentration greater than 20 μmol/g of dry tissue in the basal liver biopsy achieved histological improvement following mild iron depletion.

Some authors reported a high correlation between the baseline levels of ALT and their reduction after treatment and a trend towards a greater ALT reduction in patients with the highest baseline serum ferritin values.^[9,11] The possible effect of a low-iron diet (5–7 mg of iron per day) without phlebotomy in chronic hepatitis C has also been studied. Sumida et al.^[21] demonstrated that, in patients under a low-iron diet for 6 months, a significant decrease in ALT levels was achieved, although to a lesser extent than that achieved by phlebotomies.

As it is known that iron absorption is significantly increased in an iron-deficient state,^[23] several studies combined phlebotomies with a low-iron diet.^[17,18,24] It has been demonstrated that this combination induces an additional effect in iron reduction therapy for chronic hepatitis C. Furthermore, a high percentage of ALT normalisation (69%) was obtained with this combination.^[18] In one study, it was reported that, in patients with chronic hepatitis C and a partial response to phlebotomy, the addition of ursodeoxycholic acid (UDCA) might improve the biochemical parameters.^[25] A decrease in ALT levels by phlebotomy was observed from 137 ± 72 to 75 ± 23 IU/L and a further significant reduction to 42 ± 16 IU/L after combination with UDCA.

Also, phlebotomy may lower risk of development of hepatocellular carcinoma (HCC). Kato et al.^[18] treated 35 patients with chronic hepatitis C with weekly phlebotomy (200 mL), followed by maintenance phlebotomy for 44–144 months and a low-iron diet and they also studied a control group of 40 untreated chronic hepatitis C. They observed development of HCC in 8.6% of patients of the phlebotomy group and in 39% of the control group after 10 years of follow-up (P < 0.05).
In summary, all these data suggest that treatment with phlebotomy and low-iron diet during a prolonged time (3 years or more) may be useful for patients with chronic hepatitis C who are not eligible for PEG-IFN-based anti-viral therapy.

Ursodeoxycholic Acid
Ursodeoxycholic acid has a direct protective effect on hepatocytes against apoptosis induced by endogenous bile acids and stimulates bile acid secretion hence reducing retention of toxic bile acids and therefore, cell injury.^[26] Regarding HCV infection, Takano et al.^[27] reported a randomised, controlled-dose trial in naïve patients with chronic hepatitis C who received 150 (n = 20), 600 (n = 18) or 900 (n = 19) mg/day of UDCA for 16 weeks. A significant decrease in ALT and gamma-glutamyl transpeptidase (gamma-GTP) levels was observed with doses of 600 and 900 mg compared to 150 mg, but serum HCV-RNA remained unchanged. The adverse effects of UDCA were not serious and the doses used were well tolerated. In another controlled study, 18 patients were treated with 600 mg/day of UDCA for 12 months and a significant reduction in serum aminotransferases and gamma-GTP values during UDCA treatment was found compared with the placebo group.^[28] However, liver biopsies performed after 12 months of therapy did not demonstrate an improvement in the histological activity index scores with respect to the basal liver sample. Probably, the interval between both paired liver biopsies was too short to prove the effects of UDCA treatment on liver histology.

The majority of the posterior studies have confirmed that UDCA treatment in chronic hepatitis C decreases serum ALT and gamma-GTP levels, although with no anti-viral effect, 600 mg/day being the preferred UDCA dose.^[29–36] However, in a large double-blind trial, 596 patients with chronic hepatitis C (including nonresponders to IFN treatment) were treated with UDCA at 150, 600 or 900 mg/day for 24 weeks and it was found that, although changes in ALT and aspartate amino transferase (AST) were similar between doses of 600 and 900 mg/day, gamma-GTP decreased significantly more in the group receiving 900 mg/day.^[34] This suggests that increasing UDCA dose up to 900 mg/day may have additional benefits without compromising safety of therapy. Sato et al.^[35] performed a dose-up trial from 600 mg to 900 mg/day of UDCA in patients with chronic hepatitis C (n = 25) or compensated liver cirrhosis (n = 7) for 24 weeks and reported that administration of 900 mg/day was more effective than 600 mg/day of UDCA for reducing aminotransferases and gamma-GTP levels.
In most of the published trials, UDCA was administered for 24 weeks, but longer treatment periods (12 and 24 months) are well tolerated and safe.^[28,32,33] Omata et al.^[34] prolonged UDCA therapy up to 104 weeks in 247 patients. In this extended period, an initial dose of 600 mg/day was adopted that could be increased to 900 mg/day. The authors observed a maintained decrease in ALT, AST and gamma-GTP over that period. Unfortunately, it was not reported in how many of those patients the UDCA dose was increased to 900 mg/day and neither whether adverse events were more severe or not. In our clinical experience, treatment of patients with chronic hepatitis C with higher UDCA doses (up to 20 mg/kg/day) and for longer periods (more than 5 years) is well tolerated and safe, and may induce a persistent decrease in the biochemical parameters.

Only few articles have studied the predictive factors of response to UDCA in chronic hepatitis C, but results should be taken with caution because of the different UDCA schedules used and the heterogeneity of the patients (naïve patients, nonresponders to previous IFN therapy and patients with liver cirrhosis.). Thus, a better response to treatment has been associated with low basal ALT levels, high basal values of gamma-GTP, low histological activity index scores or even with the presence of liver cirrhosis.^[32–34] Also it was found that the response was independent of HCV genotypes or HCV-RNA levels.^[32,33]
 
As levels of aminotransferases have been associated with progression of liver fibrosis,^[37] the decrease in ALT levels with UDCA treatment could reduce the risk of development of HCC. Tarao et al.^[38] showed that, in 56 patients with early-stage liver cirrhosis due to HCV infection who received UDCA for 37.3 ± 15.9 months, the cumulative incidence of HCC over 5 years was significantly lower (10/56: 17.9%) than in the group of 46 patients who did not received UDCA (18/46: 38%). The results suggest that UDCA treatment may prevent HCC development in patients with chronic hepatitis C. Thus, UDCA treatment may be a possible alternative for patients with chronic hepatitis C who are not candidates for currently approved anti-viral treatments.

Other Agents
Several studies have assessed the possible role of RBV monotherapy in patients with chronic hepatitis C, either naïve or nonresponders to anti-viral therapy. These studies administered RBV twice daily, most of them using a dose of 1000–1200 mg.^[39–49] The treatment duration oscillated between 12 weeks up to 24 months.^[39,46] A significant decrease in ALT levels was observed in these studies, ranging from 30% (only 2 or 4 weeks of treatment) to 75%.^[47,48] The frequency of ALT normalisation during treatment usually was around 40–60%,^[44,45,48] reaching 66% after 24 months of treatment.^[46] The mean time to ALT normalisation was approximately 8 weeks,^[40,43,44] but in the majority of the studies, ALT levels returned to pre-treatment values in all patients within 2–3 months after discontinuation of therapy.^[40,43–46] During treatment, no effect of RBV on HCV-RNA was observed in most of the trials.^{[42–46,48,49]} It has also been reported that patients with basal lower levels of ALT and of serum HCV-RNA responded more frequently.^[44,45] Regarding liver histology, several studies demonstrated an improvement in hepatic inflammation and necrosis when comparing basal and final liver biopsies,^[42,44–46] especially among those patients who normalised ALT values, although no changes in fibrosis were noted.^[46,49] It should be remarked that an increase in hepatic iron has been documented in patients under RBV therapy.^[46,49] The most frequent secondary effects of RBV treatment were haemolysis, anaemia, skin disorders (pruritus, rash, dry skin), nervous system disorders (depression, insomnia, somnolence, vertigo), increases in bilirubin concentration, uric acid and platelets.^[43,45,49] All these effects disappeared when treatment was stopped.

In summary, RBV may decrease ALT levels and may improve liver histology in a proportion of patients with chronic hepatitis C. However, taking into account the relatively small number of patients included, the short administration period and the potentially harmful of hepatic iron accumulation with RBV treatment, the general use of this drug as monotherapy cannot be recommended for chronic hepatitis C.

Colchicine was found to be an anti-fibrotic agent in animal models. However, a meta-analysis of 15 randomised clinical trials concluded that colchicine should not be used, as it has no beneficial effect on liver fibrosis.^[50]
 
Amantadine is a symmetric tricyclic amine that inhibits replication of influenza A virus. This drug has been administered as monotherapy to naïve patients with chronic hepatitis C or nonresponders to IFN or IFN/RBV treatment, at doses of 200 mg/day for 6 or 12 months.^[51–54] In all these studies, although no anti-viral effect was found, a significant decrease in ALT levels was observed with respect to basal values. However, the total number of patients treated with amantadine alone is low and hence its use cannot be recommended.

The metabolic syndrome, which includes hepatic steatosis, hypercholesterolaemia, hypertriglyceridaemia and insulin resistance/diabetes, is a common feature in patients with chronic hepatitis C.^[55] As the metabolic syndrome is associated with hepatic inflammation and fibrosis,^[56] it is important to assess and lower increased cholesterol, triglycerides and glucose concentrations. Statins are potent drugs for reducing circulating low-density lipoprotein cholesterol levels. Statins also have anti-inflammatory, antioxidant and anti-thrombotic effects.^[57] Clinical studies have reported controversial results on the activity of statins against HCV.^[58–67] However, statins must be prescribed for high cholesterol levels to HCV-infected patients, as hypercholesterolaemia is associated with steatosis and potential progression of liver disease.

Pioglitazone and metformin are used to improve glycaemic control in patients with type-2 diabetes. Chojkier et al.^[68] studied whether pioglitazone has an anti-viral effect in chronic HCV infection. They included 20 overweight patients with genotype 4 chronic hepatitis C who received 30 mg daily of pioglitazone for 14 days. Serum HCV-RNA and ALT values were significantly decreased at the end of therapy with respect to basal levels. Metformin has been proven to be effective in reducing the incidence of HCC in patients with HCV-related cirrhosis and with type 2 diabetes.^[69] Both drugs seem to have a beneficial effect on liver disease progression in patients with chronic hepatitis C and type-2 diabetes, although further evidences are needed to confirm these findings.

Antioxidants
Oxidative stress is thought to play a role in the pathogenesis of chronic hepatitis C because oxidative stress occurs early during HCV infection and increases with disease progression and severity.^[70] Vitamin deficiencies are common among patients with chronic hepatitis C and thus vitamin supplementation provides a basis for their therapeutic use.^[71] Vitamins C, D and E are the most investigated as antioxidant therapy in chronic liver diseases. However, there are no studies on the efficacy of vitamin C as monotherapy, while vitamin D did not show beneficial effect when administered to patients with chronic hepatitis C.^[72] Vitamin E (1200 IU/day) administration for 8 weeks to nonresponder patients to IFN significantly decreased the index of oxidative stress in liver biopsy, but did not significantly affect ALT levels, HCV-RNA titres or the histological degree of hepatocellular inflammation or fibrosis.^[73] However, in another study, vitamin E at doses of 800 IU/day for 12 weeks reduced serum ALT values by 46% (and AST by 35%) at the end of treatment, although ALT and AST returned to baseline levels 1 month after therapy discontinuation.^[74] Oral vitamin E supplementation (500 mg/day) given for 3 months resulted in modest reduction in serum ALT levels and improved oxidative stress in those patients with initial ALT levels >70 IU/L.^[75] In patients with HCV-related cirrhosis, bedtime administration of 900 IU/day vitamin E for 6 months almost normalised ALT values, but only in the vitamin E-deficient individuals.^[76]
 
The preventive effect of vitamin E on hepatocarcinogenesis has been investigated in patients with HCV-related liver cirrhosis. ALT levels, platelet counts, serum albumin and total cholesterol were not different compared with controls, untreated patients during the 5-year survey. The administration of vitamin E did not improve liver function, suppress hepatocarcinogenesis or improve cumulative survival.^[77] Vitamin E is nontoxic even at elevated doses (≥500 mg/day) over extended periods of time (from 6 months up to 5 years).^[73–77] On the other hand, the efficacy of vitamin E is more evident among patients with vitamin E deficiency and in those with moderately elevated ALT values.^[75]
 
When combined, daily supplementation with vitamin C (500 mg) and vitamin E (800 mg) plus zinc (40 mg) for 6 months reduced ALT values in previously untreated HCV patients.^[78] In contrast, daily doses of ascorbic acid (500 mg), D-alpha-tocopherol (945 IU) plus selenium (200 μg) for 6 months had no significant effects on ALT values or the viral load.^[79] The hepatoprotective and anti-inflammatory effects of silybin-phospholipids and vitamin E complex (SPV complex) have been investigated in patients with chronic HCV infection. SPV complex administered for 3 months had a significant and persistent reduction in ALT and AST serum levels.^[80]
 
Multi antioxidant (glycyrrhizin, schisandra, silymarin, ascorbic acid, lipoic acid, l-glutathione and alpha-tocopherol) oral daily treatment for 20 weeks may decrease viral load and ameliorate necro-inflammation in some patients.^[81] Combined oral and intravenous antioxidant therapy was associated with a decline in ALT levels and mild anti-inflammatory effects in chronic hepatitis C patients who were nonresponders to IFN.^[82] Other antioxidants, such as resveratrol and astaxanthin, are not suitable as an antioxidant therapy for chronic hepatitis C.^[83]
 
In conclusion, the data available suggest some benefits of vitamin E in reducing serum ALT concentrations, most likely in cases with vitamin E deficiency. Most studies involving antioxidant therapy (including vitamin supplementation other than vitamin E) failed to show any beneficial effect on HCV-RNA levels or liver histology in chronic hepatitis C.^[71,84] The results of the clinical studies are difficult to interpret because of the small sample sizes, short follow-up duration, inadequate end points and, finally, failure to demonstrate tissue delivery and antioxidant efficacy.^[85]
 
Other compounds like S-adenosyl-methionine or acetylcysteine when administered alone do not show significant effect on ALT levels,^[86,87] and hence their use is not recommended.

Immune Modulators and Cytokines
Viusid, a nutritional supplement, may improve oxidative stress and immunological parameters in patients with chronic hepatitis C. In patients with HCV-related decompensated cirrhosis, it seems to improve survival, disease progression and prevent HCC development. However, low numbers of patients have been analysed and the studies did not show effects on HCV-RNA levels.^[88,89]
Interleukin (IL)-10 is a cytokine that down-regulates the pro-inflammatory immune response and has a modulatory effect on liver fibrogenesis. IL-10 treatment induced ALT normalisation in 86% of patients and improved liver histology, but an increase in HCV-RNA was observed.^[90,91] Hence, IL-10 treatment is discouraged for patients with chronic hepatitis C.

Interleukin-12 and Thymosin alpha 1 have also been administered to patients with chronic hepatitis C, with no effects on ALT values or HCV-RNA levels.^[92–94] Other molecules with immunomodulatory properties, such as the glycoconjugate AM3, have been investigated in vitro,^[95] but not administered therapeutically to patients with chronic hepatitis C.

Conclusions
Several approaches may be used to treat patients with chronic hepatitis C who are not candidates for PEG-IFN based therapy. Phlebotomies in combination with a low-iron diet may induce a beneficial effect. If a favourable response is achieved, a deficiency iron status should be maintained over a prolonged period. UDCA, at dose of 900 mg, may be useful in the management of these patients. Glycyrrhizin may be considered, but the intravenous administration route implies a limitation for its general use. Metabolic disorders, if present (increased levels of cholesterol, triglycerides, glucose), must be treated. In overweight patients with chronic hepatitis C, a diet to reduce weight is desirable. Physical exercise, even if no weight is lost, may be recommended in these patients. Finally, coffee consumption is helpful, while alcohol intake and smoking are strictly forbidden.