November 6, 2013

Gastroenterology

Article in Press

Gregory T. Everson,Karen D. Sims,Maribel Rodriguez-Torres,Christophe Hézode,Eric Lawitz,Marc Bourlière,Veronique Loustaud-Ratti, Vinod Rustgi,Howard Schwartz,Harvey Tatum,Patrick Marcellin,Stanislas Pol,Paul J. Thuluvath,Timothy Eley,Xiaodong Wang,Shu-Pang Huang,Fiona McPhee,Megan Wind-Rotolo,Ellen Chung,Claudio Pasquinelli,Dennis M. Grasela,David F. Gardiner

Received 22 August 2013; received in revised form 21 October 2013; accepted 26 October 2013. published online 01 November 2013.
Accepted Manuscript

Abstract

Background & Aims

The combination of peginterferon and ribavirin with telaprevir or boceprevir is the standard treatment of hepatitis C virus (HCV) genotype 1 infection. However, these drugs are not well tolerated, producing side effects and suboptimal virologic responses. In a phase 2a, open-label study, we examined safety and efficacy of an interferon-free, ribavirin-free regimen of direct-acting antivirals, comprising daclatasvir (an NS5A replication complex inhibitor), asunaprevir (an NS3 protease inhibitor), and BMS-791325 (a non-nucleoside NS5B inhibitor), in patients with chronic HCV infection.

Methods

We analyzed data on 66 treatment-naive patients with HCV genotype 1 infection without cirrhosis who were randomly assigned to groups given daclatasvir (60 mg, once daily), asunaprevir (200 mg, twice daily), and BMS-791325 (75 or 150 mg, twice daily) for 12 or 24 weeks. The primary endpoint was HCV RNA <25 IU/mL at 12 weeks after treatment (SVR12).

Results

In 64 patients, levels of HCV RNA were <25 IU/mL by week 4 of treatment (including 48/49 patients with HCV genotype 1a infection and 45/46 patients with the non-CC IL28B genotype). Sixty-one patients (92%) achieved SVR12, based on a modified intention-to-treat analysis. Virologic responses were similar between 12 and 24 weeks of treatment. During the study, 2 patients experienced viral breakthrough and 1 patient relapsed. There were no grade 3–4 increases in levels of alanine or aspartate aminotransferase or bilirubin; there were no deaths or discontinuations due to serious adverse events or adverse events related to the treatment regimen. The most common adverse events were headache, asthenia, and gastrointestinal symptoms.

Conclusions

In a phase 2a study, the all-oral, interferon- and ribavirin-free regimen of daclatasvir, asunaprevir, and BMS-791325 was well tolerated and achieved high rates of SVR12 in patients with HCV genotype 1 infection. Further studies of this regimen are warranted.

Keywords: liver disease, therapy, DAA, drug combination

Abbreviations: APRI, aminotransferase: platelet ratio, GT, genotype, HCV, hepatitis C virus, SVR, sustained virologic response

No full text is available. To read the body of this article, please view the PDF online.

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Gastroenterology

Article in Press

Stefan Zeuzem,Thomas Berg,Edward Gane,Peter Ferenci,Graham R. Foster,Michael W. Fried,Christophe Hezode,Gideon M. Hirschfield, Ira Jacobson,Igor Nikitin,Paul J. Pockros,Fred Poordad,Jane Scott,Oliver Lenz,Monika Peeters,Vanitha Sekar,Goedele De Smedt, Rekha Sinha,Maria Beumont-Mauviel

Received 4 July 2013; received in revised form 24 October 2013; accepted 29 October 2013. published online 04 November 2013.
Accepted Manuscript

Abstract

Background & Aims

Simeprevir (TMC435) is an oral NS3/4 protease inhibitor in Phase III trials for chronic hepatitis C virus (HCV) infection. We performed a Phase IIb, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of the combination of simeprevir, peginterferon-α2a (PegIFN), and ribavirin (RBV) in patients with HCV genotype-1 infection previously treated with PegIFN and RBV.

Methods

We analyzed data from patients who did not respond (null response), had a partial response, or relapsed following treatment with PegIFN and RBV, randomly assigned to receive simeprevir (100 or 150 mg, once daily) for 12, 24, or 48 weeks plus PegIFN and RBV for 48 weeks (n=396), or placebo plus PegIFN and RBV for 48 weeks (n=66). All patients were followed for 24 weeks after planned end of treatment; the primary endpoint was the proportion of patients with sustained virologic response (undetectable HCV RNA) at that timepoint (SVR24).

Results

Overall, SVR24 rates were significantly higher in the groups given simeprevir than those given placebo (61%–80% vs 23%;P<.001), regardless of prior response to PegIFN and RBV (simeprevir vs placebo: prior null response, 38%–59% vs 19%; prior partial response, 48%–86% vs 9%; prior relapse, 77%–89% vs 37%). All groups had comparable numbers of adverse events; these led to discontinuation of simeprevir or placebo and/or PegIFN and RBV in 8.8% of patients given simeprevir and 4.5% of those given placebo.

Conclusions

In treatment-experienced patients, 12, 24, or 48 weeks simeprevir (100 mg or 150 mg once daily) in combination with 48 weeks PegIFN and RBV significantly increased rates of SVR24 compared to patients given placebo, PegIFN, and RBV and was generally well tolerated.

ClinicalTrials.gov number: NCT00980330

Keywords: direct-acting antivirals, DAA, clinical trial, SVR24

Abbreviations: AE, adverse event, ASPIRE, Antiviral STAT-C Protease Inhibitor Regimen in Experienced patients, AUC, area under the curve, BMI, Body Mass Index, EOT, End of treatment, FSS, Fatigue Severity Scale, HCV, hepatitis C virus, HIV, human immunodeficiency virus, IC50, median inhibitory concentration, LLOQ, lower limit of quantification, PegIFN, Peginterferon-α2a, PegIFN-α, Peginterferon-α,PILLAR, Protease Inhibitor TMC435 study assessing optimaL dose and duration as once-daiLy Antiviral Regimen, QD, once daily, RBV,ribavirin, RVR, rapid virologic response, SMV, simeprevir, SVR, sustained virologic response, SVR24, sustained virologic response at 24 weeks after the planned end of treatment, ULN, upper limit of normal

No full text is available. To read the body of this article, please view the PDF online.

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'There is no doubt we are on the verge of wiping out hepatitis C,' researchers say

By Catholic Online (NEWS CONSORTIUM)
11/6/2013
Catholic Online (www.catholic.org)

Hepatitis C, a silent, deadly illness that kills more Americans annually than AIDS, is the leading condition behind liver transplants. There is reason to hope with the introduction of a new medication that has had remarkable success in clinical trials. "There is no doubt we are on the verge of wiping out hepatitis C," Dr. Mitchell L. Shiffman says, the director of the Bon Secours Liver Institute of Virginia.

LOS ANGELES, CA (Catholic Online) - In the course of the next three years, new drugs are expected to come to be made available that will cure most patients with the virus. In some cases, one pill a day will all that it will take . and with only minimal side effects.

Current treatments for Hepatitis C cure about 70 percent of newly treated patients - but require six to 12 months of injections that can bring debilitating side effects.

The new drugs are expected to cost from $60,000 to more than $100,000 for a course of treatment. For the uninsured or those in developing countries, access to these drugs may prove to be difficult.

Many of those afflicted find themselves in a "Catch 22:" Even when discounts or generic drugs are offered to poor countries, there are no international agencies or charities that buy hepatitis C medications, as there are for H.I.V. and malaria drugs.

Some express concern that the bill will be run up when large numbers of people who have maintained without the new drugs will suddenly turn to them. Many people infected with hepatitis C never suffer serious liver problems.

"The vast majority of patients who are infected with this virus never have any trouble," Dr. Ronald Koretz, emeritus professor of clinical medicine at the University of California, Los Angeles says.
Currently it's not possible to tell in advance whether an infected individual will go on to suffer serious consequences. For patients who can afford the new drugs, the temptation to take them before trouble arises will be powerful.

An estimated three to four million Americans are infected with hepatitis C. About 150 million, which are three to five times the number who have H.I.V. Have hepatitis C worldwide. Most people who are infected do not know it, because it can take decades for the virus to damage the liver sufficiently to cause symptoms.

The number of new infections in the United States has fallen to about 17,000 a year, from more than 200,000 per year in the 1980s, according to the Centers for Disease Control and Prevention. There has been a recent rise in cases among young people who inject pain medicines or heroin.

About 16,600 Americans had hepatitis C listed as a cause of death on death certificates in 2010, but this may only represent a small fraction. According to the Centers for Disease Control, while there are fewer new infections, the number of deaths is expected to keep rising as the infections incurred years ago increasingly take their toll.

Hepatitis C is spread chiefly through the sharing of needles, although it can also be acquired during sex. The virus was transmitted through blood transfusions before testing of donated blood began in 1992.

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Drug Trio Works in Low-Response Hepatitis C

Meeting Coverage

Published: Nov 6, 2013

Coverage of Hepatitis C Virus is supported in part by an independent educational grant from AbbVie Pharmaceuticals.

This report is part of a 12-month Clinical Context series.

Action Points

  • Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
  • Note that this uncontrolled study of patients with refractory genotype 2 or 3 HCV demonstrated high efficacy rates when sofosbuvir was added to interferon and ribavirin therapy.
  • Be aware that there is great interest in interferon-free regimens given the high adverse event rate associated with this medication.

WASHINGTON -- An unlikely drug combination had high efficacy rates in a hard-to-treat group of patients with hepatitis C virus (HCV) infection, a researcher said here.

After 12 weeks of therapy, the combination -- sofosbuvir, pegylated interferon, and ribavirin -- led to viral cure rates of 89%, according to Eric Lawitz, MD, of the University of Texas Health Science Center in San Antonio.

Patients in the study were regarded as hard to treat because they had genotype 2 and 3 disease, had failed previous therapy with interferon and ribavirin, and many had cirrhosis, Lawitz said at the annual meeting of the American Association for the Study of Liver Diseases.

The standard current therapy is interferon and ribavirin, combined with one of two approved protease inhibitors that target the virus itself -- telaprevir (Incivek) and boceprevir (Victrelis).

Sofosbuvir remains investigational but it has mainly been tested in combination with ribavirin alone, as part of the movement to get rid of the highly toxic interferon.

The drug has been recommended for approval, with different indications depending on HCV genotype. An FDA advisory panel suggested it be used with interferon and ribavirin in genotype 1 patients, but with ribavirin alone in genotypes 2 and 3.

But it seems unlikely the drug will often be used in combination with interferon and ribavirin, commented Donald Jensen, MD, of the University of Chicago, who was not involved in the study but who moderated the session at which it was presented.

"Certainly, the field is moving toward an interferon-free world." he told MedPage Today. But there might still be cases in which an interferon-based regimen might be used as a "fallback," he added.

"If you have a genotype 3 patient with cirrhosis who had failed therapy with sofosbuvir and ribavirin," he said, interferon might be added to a retreatment regimen.

The study "shows you can use it," he said.

In a single-arm study, Lawitz and colleagues enrolled 47 patients for 12 weeks of therapy with the three drugs. The primary endpoint was undetectable virus 12 weeks after the end of therapy (SVR12).

The overall SVR12 rate was 89%, with 22 of the 23 genotype 2 patients reaching the endpoint and 20 of 24 genotype 3 patients -- 96% and 83% respectively.

Lawitz reported that one genotype 2 patient was noncompliant with the medication and stopped treatment early.

Two genotype 3 patients also stopped early -- one lost to follow-up and one because of an adverse event -- while two others completed therapy but relapsed before the end of the 12-week follow-up.

SVR12 rates were similar between cirrhotic and non-cirrhotic patients, Lawitz reported.

Almost all patients reported some adverse events, "not unexpectedly in an interferon-based regimen," Lawitz said, adding the adverse event profile was consistent with the known side effects of interferon and ribavirin.

The most common events were flu-like symptoms, fatigue, anemia, neutropenia, and nausea, Lawitz reported.

The study was supported by Gilead Sciences. Lawitz reported financial links with AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Idenix Pharmaceuticals, Intercept Pharmaceuticals, Janssen, Merck, Novartis, Presidio, Roche, Santaris Pharmaceuticals, Vertex Pharmaceuticals, Kadmon, Achillion Pharmaceuticals, BioCryst, Biotica, Enanta, Idenix, and Theravance. Several authors are employees of Gilead.

Jensen reported financial links with Abbott, Roche/Genentech, Vertex, GlobeImmune, Boehringer-Ingelheim, and Tibotec.

Primary source: American Association for the Study of Liver Diseases
Source reference: Lawitz E, et al "Sofosbuvir in combination with pegIFN and ribavirin for 12 weeks provides high SVR rates in HCV-infected genotype 2 or 3 treatment experienced patients with and without compensated cirrhosis: Results from the LONESTAR-2 study"AASLD 2013; Abstract LB-4.

Source

Studies 'Validate' CDC HCV Testing Advice

Meeting Coverage

Published: Nov 6, 2013

By Ed Susman , Contributing Writer, MedPage Today

179244038

WASHINGTON -- Thousands of people in the U.S. -- including an estimated 50,000 veterans -- are infected with the hepatitis C virus (HCV), and don't know it, researchers reported here.

In one study, an estimated 900,000 veterans who were seen in the previous year at a Veterans Affairs facility had not been screened for the virus, and of that group, an estimated 51,000 may be infected and unaware of their status, Lisa Backus, MD, PhD, deputy chief consultant for measurement and reporting in the Office of Public Health at VA Palo Alto Health Care System, Palo Alto, California, told MedPage Today.

A second study, also reported here at the American Association for the Study of Liver Diseases, indicated that one of every eight patients born between 1945 and 1965 and treated in the emergency room tested positive for the virus that causes liver disease, reported James Galbraith, MD, associate professor of emergency medicine at the University of Alabama-Birmingham.

In discussing the studies at a press briefing, Gregory Fitz, MD, president of the AASLD and chief of internal medicine at the University of Texas Southwestern Medical School, Dallas, said that since HCV infection is treatable and curable it is important to determine who has the disease so they can initiate therapy.

The two studies help validate the CDC HCV testing recommendations, Fitz said. "The CDC had come out with birth cohort guidelines that basically say if you were born between 1945 and 1965 you ought to be tested for hepatitis C at least once in your life because in that age cohort the probability of finding that virus is increased."

Michael Fried, MD, professor of medicine at the University of North Carolina, Chapel Hill, told MedPage Today that birth cohort testing removes from physicians the sometimes difficult task of asking people about what might be considered embarrassing questions. Instead, the CDC recommends testing anyone in the age bracket.

"People who donate blood and whose blood has not been rejected have been tested for HCV, and other viruses, and probably can be confident they don't have hepatitis C," Fried said. However, Backus suggested that even if a person has given blood in the past 5 years, a formal test for hepatitis C should still be performed.

In her study, Backus reported that 64.2% of the veterans born in the critical 1945-1965 era have been screened for HCV and 54.7% of all veterans have been screened for the virus. "This is a substantially better screening rate than in the general public clinics," she said. "Those screening levels for HCV are around 8%-9%, and about 2% of those patients in the 1945-65 birth cohort tested positive."

Backus reviewed outcomes in the screening of 5.5 million veterans in VA care. Overall, about 6.1% of the veterans screened were found to harbor infection with HCV. About 1.7% of those born before 1945 have the virus; 9.9% of those in the 20-year birth cohort have the virus, and 1.1% of those born after 1965 are infected.

"Extrapolating the most recent 1945-1965 birth cohort for HCV prevalence (5.7%) to those veterans who have not been screened – 905,571 – suggests that up to 51,000 additional veterans in VA care could be identified with HCV infection with complete birth cohort screening," Backus said.

"We advise the public to ask their doctor to test them for hepatitis C infection," she said. "And we tell doctors to test patients in the birth cohort, and not to assume that the patient is not at risk for infection."

In the Alabama study, Galbraith and colleagues screened all people who came to the emergency room. In 6 weeks, they screened just over 984 patients who were unaware of their hepatitis C status; 112 tested positive and 71 of those who tested positive -- 72% -- proved to have hepatitis C infection.

Commented Fitz: "So you have an enormous reservoir of people out there who have hepatitis C. And these were people who came into the emergency room not because they thought they had hepatitis but because of something else.

Galbraith and Backus had no disclosures.

Fitz had no disclosures.

Fried disclosed commercial relationships with Gilead, Vertex, Bristol-Myers Squibb, Merck, Genentech, Janssen and Abbott.

Primary source: American Association for the Study of Liver Diseases
Source reference: Galbraith J, et al "Screening in emergency department identifies a large cohort of unrecognized chronic hepatitis C virus Infection among baby boomers" AASLD2013.

Additional source: American Association for the Study of Liver Diseases
Source reference:Backus L, et al "Hepatitis C virus screening and prevalence among US veterans in Department of Veterans Affairs Care in 2012" AASLD 2013.

Source

Provided by Oncology Nurse Advisor

Kathy Boltz, PhD

November 04, 2013

Researchers have isolated and characterized the progenitor cells that give rise to malignant hepatocellular carcinoma tumors long before the actual tumors can be detected. These results may have profound implications for the diagnosis and treatment of hepatocellular carcinoma, the most common form of liver cancer.

Hepatocellular carcinoma develops slowly and often does not produce symptoms until it is at an advanced stage, making it difficult to diagnose. Although treatments are available for the early stages, no effective treatment exists for the advanced stages of hepatocellular carcinoma, which is usually fatal within 3 to 6 months of diagnosis.

An estimated 30,000 new cases of liver cancer are diagnosed annually in the United States, mostly in men. More than 21,600 Americans die from liver cancer each year and that rate has doubled over the past 20 years. Hepatocellular carcinoma is the third leading cause of cancer-related deaths worldwide.

Michael Karin, PhD, of the University of California, San Diego School of Medicine and his colleagues found that hepatocellular carcinoma progenitor cells occur in dysplastic liver lesions in mouse models of hepatocellular carcinoma. Liver damage in humans can be caused by viral infections such as hepatitis or chronic alcohol abuse.

"It was never established whether dysplastic lesions are just a regenerative (healing) response of the liver triggered by tissue damage or are actually premalignant lesions that harbor tumor progenitor cells," said study coauthor Debanjan Dhar, PhD, a postdoctoral researcher in Karin's laboratory. "Here we show that hepatocellular carcinoma progenitor cells are likely derived from dysplastic lesions, can progress to malignant tumors, and further demonstrate that the malignant progression of hepatocellular carcinoma progenitor cells to full-blown liver cancer depends upon the microenvironment that surrounds them."

The researchers characterized the progenitor cells based on several biomarkers that distinguish them from normal cells, and identified cellular signaling pathways critical for development of the cells' malignant potential. Elevated expression of LIN28, a regulatory protein, is required for production of autocrine IL-6, a cytokine involved in cell signaling; together, they control the development of progenitor cells into hepatocellular carcinoma cells. Cells with elevated LIN28 and IL-6 expression exist in both mouse and human premalignant liver lesions.

Researchers were able to detect potential malignant lesions in needle biopsies of a subset of patients infected with the hepatitis C virus who had not developed hepatocellular carcinoma. Hepatitis C is a major risk factor for hepatocellular carcinoma development.

Dhar said that identifying premalignant lesions in high-risk patients based on markers associated with the progenitor cells would allow for earlier detection as well as therapeutic interventions. "Better understanding of … the cellular networks will provide us with new and effective therapeutic targets … therapies can be developed to specifically eliminate the hepatocellular carcinoma progenitor cells even before a tumor has developed."

This study was published in Cell (2013; doi.org/10.1016/j.cell.2013.09.031).

Source

The botanical compound achieves a major milestone in drug development in the US

November 05, 2013 09:00 AM Eastern Standard Time

WASHINGTON--(BUSINESS WIRE)--Shanghai Sundise Traditional Chinese Medicine Co. Ltd released its multi-center, double-blinded, placebo-controlled clinical phase II trial results at a satellite symposium during the 2013 annual meeting of the American Association for the Study of Liver Diseases (AASLD®). The results indicate that in chronic hepatitis C patients with moderate to severe fibrosis Fuzheng Huayu tablet (FZHY) is safe, well tolerated and tended to stabilize and improve liver fibrosis, making FZHY the first traditional Chinese medicine compound to complete such clinical studies in the treatment of liver diseases.

“This study assured us about the safety and tolerability of FZHY and its previously reported effects on liver fibrosis in chronic hepatitis patient populations”

Hepatitis C is the major cause of liver fibrosis, cirrhosis and ultimately hepatocellular carcinoma (HCC) in the US. Newly approved direct-acting antiviral agents may effectively clear hepatitis C virus. However, the effects on underline liver fibrosis and cirrhosis remain to be seen. Currently, there is no FDA approved antifibrosis therapy. FZHY is a botanical compound approved in China for liver fibrosis caused by hepatitis B virus infection. This is the first clinical phase II trial of FZHY as a botanical drug to assess the safety, tolerability, and efficacy on fibrosis in HCV patients who have been previously failed by the anti-viral therapies, cannot receive or refused Interferon-based therapy. The trial was initiated in 2010 to evaluate FZHY with treatment protocol for one year and pre- and post-treatment liver biopsy assessments. The trial was funded by Shanghai Sundise Traditional Chinese Medicine Co. Ltd, with eight US medical institutions and a team of world-famous liver specialists working together. Detailed trial information is available at www.clinicaltrials.gov (Identifier: NCT00854087).

“This study assured us about the safety and tolerability of FZHY and its previously reported effects on liver fibrosis in chronic hepatitis patient populations,” stated Tarek Hassanein, MD., director of SCTI Research Foundation and lead principal investigator. “This study is a pivotal trial in bridging Eastern and Western medicine.”

“Our company took a unique approach in developing botanical medicines that are safe, effective and affordable,” said Huashi Bian, CEO and president of Shanghai Sundise. “This important milestone has positioned us in the innovative drug development area in the US.”

Prof. Ping Liu, one of the inventors of FZHY from Shanghai University of Traditional Chinese Medicine, indicated, “The long history of clinical usage and evidence-based clinical studies in China has supported this US phase II trial with sufficient data in safety and efficacies.”

FZHY is developed by Shanghai Sundise Traditional Chinese Medicine, Co., Ltd. which holds seventeen patents including five worldwide ones.

Shanghai Sundise Traditional Chinese Medicine Co., Ltd. is a technology corporation specialized in the modernization of Traditional Chinese Medicine, based in Shanghai, China. Sundise works closely with universities and research institutes across China and the United States to conduct studies on therapeutic compounds based on the Chinese traditional medicine. Learn more about Sundise and its products at http://www.sundise.com.

FDA: US Food and Drug Administration
AASLD: American Association for the Study of Liver Diseases

Contacts

Shanghai Sundise Traditional Chinese Medicine Co., Ltd.
Jiayi Zhang, +86-21-52896028
jiayi.zhang@sundise.com

Source

Fixed-Dose HCV Combo OK With Ribavirin Substitute

Meeting Coverage

Published: Nov 5, 2013 | Updated: Nov 5, 2013

Coverage of Hepatitis C Virus is supported in part by an independent educational grant from AbbVie Pharmaceuticals.

By Michael Smith, North American Correspondent, MedPage Today

Reviewed by F. Perry Wilson, MD, MSCE; Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

WASHINGTON -- A fixed-dose combination of two investigational hepatitis C (HCV) drugs needs a boost in patients with advanced fibrosis or cirrhosis, a researcher said here.

But the boost doesn't have to be the old standby for HCV therapy, ribavirin, according to Edward Gane, MD, ofAuckland Clinical Studies in Auckland, New Zealand.

Instead, results in a small clinical trial were much the same when another investigational drug, dubbed GS-9669, was added to the combination of sofosbuvir and ledipasvir, Gane reported at the annual meeting of the American Association for the Study of Liver Diseases.

In the ELECTRON trial, Gane and colleagues are testing a single-pill combination of sofosbuvir, a nucleotide polymerase inhibitor, and ledipasvir, which blocks the nonstructural NS5A protein.

For this analysis, he reported outcomes in previously treated patients with genotype 1 HCV and advanced fibrosis or cirrhosis, who were given 12 weeks of the fixed-dose combination alone or with either ribavirin or GS-9669, a NS5B non-nucleoside inhibitor.

The primary endpoint was the proportion of patients who had undetectable virus 12 weeks after the end of therapy (SVR12).

Initially, Gane said, the researchers had tested the fixed-dose pill in 20 patients with or without ribavirin, but results were disappointing without ribavirin with SVR12 rates of 70% versus 100%.

So they enrolled another 51 patients and randomly assigned them to 12 weeks of the fixed dose combination along with either ribavirin or GS-9669.

The results here were better, Gane reported, as the SVR12 rate was 100% in both groups.

Importantly, patients receiving GS-9669 did not have the typical drop in hemoglobin that is associated with ribavirin.

Clinical adverse events were "common and mostly mild," Gane said, mainly headache, fatigue, and nausea. Lab abnormalities were also mild and grades 3 and 4 abnormalities were mostly associated with ribavirin.

In another sub-study, researchers tested the effect of the combination, along with ribavirin, in 25 treatment-naïve genotype 1 patients for only 8 weeks of treatment.

One advantage of many of the all-oral regimens under investigation is that they are quickly beneficial, with treatment duration of usually 12 or 24 weeks.

In contrast, treatment with the current standard of care -- pegylated interferon, ribavirin, and a protease inhibitor -- can be as long as 48 weeks.

In another study to be presented here, Gane said, 8 weeks of sofosbuvir, ledipasvir, and ribavirin was as efficacious as 12 weeks.

But a 6-week treatment period was too short, he said, and led to an "unacceptable relapse rate."

Both at 12 and 8 weeks, Gane said, the three drugs yielded 100% SVR12 rates, but after the 6-week course only 68% of patients reached that endpoint.

The analyses begin to fill in the picture of how the fixed-dose combination might be used, commented Gary Davis, MD, of Baylor University Medical Center in Waco, Texas, who was not involved in the study but who moderated the session at which it was presented.

But the studies remain small so they don't know how much stock can be put in them, he toldMedPage Today.

Sofosbuvir recently got the nod from an FDA advisory panel, which recommended its approval, either with interferon and ribavirin or ribavirin alone, depending on the patient.

But ledipasvir and GS-9669 remain under clinical investigation.

The study was supported by Gilead Sciences. Gane reported financial links with Roche, AbbVie, Novartis, Tibotec, Gilead, Janssen Cilag, Vertex, and Achillion. Several authors are employees of Gilead.

Davis reported financial links with Abbott, Bristol-Myers Squibb, Boehringer Ingelheim, Genentech, Gilead, Johnson&Johnson, Merck & Co, Novartis, Pharmasset, and Vertex.

Primary source: American Association for the Study of Liver Diseases
Source reference: Gane E, et al "Once daily sofosbuvir/ledipasvir fixed dose combination with or without ribavirin: the ELECTRON trial" AASLD 2013; Abstract 73.

Source

Also See: Once Daily Sofosbuvir/Ledipasvir Fixed Dose Combination with or without Ribavirin: the ELECTRON trial

Bristol-Myers Squibb First to Japan in New Hepatitis C Therapy Race

Provided by The Motley Fool

By Amy Ho | More Articles
November 5, 2013

The race for the new generation of hepatitis C treatments continues as Bristol-Myers Squibb (NYSE: BMY) takes first place in seeking approval for a truly all-oral treatment independent of interferon and ribavirin.

Gilead Sciences (NASDAQ: GILD)'s sofosbuvir and Johnson & Johnson (NYSE: JNJ)'s simprevir both made significant progress toward FDA approval by the end of this year. The oral agents have unfortunately only undergone studies in conjunction with the injectable interferon, which is associated with both its cumbersome method of delivery and unpleasant flu-like side effects. Other agents have undergone studies in combination with ribavirin, which is associated with side effects of anemia and rash. The ultimate goal is to develop a stand-alone oral agent independent of both interferon and ribavirin, achieve both ease of delivery and improved compliance and more benign side effects.

Gilead, J&J, Bristol-Myers, Merck (NYSE: MRK), AbbVie, and until recently, Vertex, were all vying to be the first in that space. However, Gilead has been the perceptual the leader of the pack due to sofosbuvir's unanimous recommendation by FDA panel last week and impressive study results; J&J's simeprevir is less far-reaching and will target a much smaller market and genotype of hepatitis C.

Bristol-Myers, however, has won the race in Japan. The company announced over the weekend its submission to Japan's Pharmaceutical and Medical Devices Agency for approval of its purely oral and interferon-free hepatitis C combination of daclatasvir with asunaprevir.

This announcement followed phase 3 data of the two drugs in 222 Japanese patients showing an 84.7% overall cure rate over 24 weeks. Japan is not a bad market to be the first for approval. According to the WHO, as compared to the 150,000 new cases annually reported in the US and Western Europe, Japan has an incidence of approximately 350,000 new cases each year. Around 1.2 million people in Japan have hepatitis C, and more than 90% of hepatocellular cancer in Japan results from hepatitis C infection, making treatment essential in this population.

The race for a cure is far from over. As Gilead and J&J expect New Drug Applications this year, Bristol-Myers plans to begin phase 3 trials of a combination of the existing daclatasvir and asunaprevir with a third agent, BMS791325, into a three-drug single pill taken over just a 12-week course. Gilead is working on its own combination therapy, and AbbVie has long had a late-stage agent in the making .

Although late to the game, Merck, in collaboration with Bristol-Myers, is making headwind in phase 2 trials as well for a new combination therapy. Responsible for current hepatitis C therapy Victrelis, albeit with struggling sales down to $502 million in 2012, Merck earned breakthrough designation for its new combination of MK-5172 and MK-8742. The first breakthrough designation drug was approved last week, giving more credibility to the new FDA program to expedite review and approval of certain drugs. Merck recently announced phase 2 data of a study showing cure rates of higher than 90% when used both with and without ribavirin. The therapy is intended to also be an all-oral agent used independent of interferon and ribavirin.

There clearly continues to be significant movements and improvements from several main players in big pharma, and this will continue throughout the year until an agent is approved. Analysts project a $20 billion market for the new therapy, and that number continues to grow as more patients are diagnosed each year and as physicians continue to hold off initiating patients on old therapies in anticipation of newer better agents. As these therapies throttle down the pipeline, the winner will be not only the markets, but also the patients.

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Source

Also See: BMS Submits First All-Oral, Interferon-Free and Ribavirin-Free Treatment Regimen for Regulatory Review in Japan for Patients with Chronic Hepatitis C Infection

Public education on acetaminophen dangers vitally important

Provided by Healio

November 6, 2013

WASHINGTON — While progress has been made in helping people recognize the potential dangers associated with acetaminophen use and its connection to acute liver failure, the idea of doctors regularly touting use of an over-the-counter treatment that was once termed a “suicide agent” in the United Kingdom remains problematic, a speaker said here.

“It’s now, ‘Tylenol: No. 1 doctor recommended,’ ” William M. Lee, MD, of the division of digestive and liver diseases at the University of Texas Southwestern Medical Center and the division of gastroenterology, hepatology and nutrition at Ohio State University, said at The Liver Meeting while showing a photo of an advertisement he saw for Tylenol and not the implication of relative safety.

“Let’s think about that … what else was doctor recommended?” he asked, forwarding his presentation to a slide of decades-old advertisements of doctors espousing the use of cigarettes with headlines such as “More doctors smoke Camels than any other cigarette” and “20,679 physicians say Luckies are less irritating.”

In delivering the Hyman J. Zimmerman Hepatotoxicity State-of-the-Art Lecture entitled “Acetaminophen and the Liver: Poison or Panacea,” Lee noted considerable progress has been made, but more must be done to reduce the annual number of acute liver failure episodes and deaths related to the drug.

In recent years, the clinical syndrome related to acetaminophen overdose has been characterized, Lee noted. And soon prognostic tests and an assay to detect unrecognized cases may be available, he said.

Despite these and other advancements, however, there has been no decline in cases observed, suggesting the importance of better understanding of acetaminophen and the potential need for further restrictions.

“I think we made some strides; I think the FDA is on board, but it’s awfully slow,” Lee said.

Among potential efforts being considered are stronger limits on daily dosing; reducing the number of pills per package and/or changing packaging to blister packs to help users better understand dosing; stronger side effect warnings, similar to those for prescription products; suggestions to begin dosing with one tablet instead of two; unbundling of opioids; limiting dosing to 325 mg; and more.

Disclosure: Lee is a consultant with Eli Lilly and Novartis, receives grant/research support from Gilead, Roche, Vertex, BI, Anadys, BMS and Merck and receives speaking/teaching funds from Merck.

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Also See:Label Warnings Not Enough to Protect Consumer Safety When Taking Acetaminophen

Provided by Healio

November 5, 2013

WASHINGTON — Patients with chronic hepatitis C genotype 1, including those with cirrhosis, experienced high rates of sustained virologic response at 12 weeks post-treatment with a safe, well-tolerated, interferon- and ribavirin-free regimen of three direct-acting antivirals in a study presented at The Liver Meeting.

In a phase 2b, open-label study, researchers randomly assigned 166 patients to triple therapy with NS5A inhibitor daclatasvir, NS3 inhibitor asunaprevir and 75 mg (n=80) or 150 mg (n=86) non-nucleoside NS5B inhibitor BMS-791325 for 12 weeks. All patients were treatment naive, had HCV genotype 1, and 9% of the cohort had biopsy-confirmed cirrhosis. Eighty-two percent of patients had genotype 1a, 67% had a non-CC IL28B genotype and 38% had a METAVIR fibrosis stage of F3 or F4. SVR at 12 weeks post-treatment was the primary endpoint.

End-of-treatment response occurred in 97.5% of the 75-mg group and 94.2% of the 150-mg group. SVR at 12 weeks was approximately 92% across the cohort, with no significant impact observed as a result of BMS-791325 dosage. Among cirrhotic patients, overall rates of SVR12 were more than 90%, regardless of genotype 1 subtype or IL28B status.

Virologic breakthrough occurred in two patients in the 75-mg group and three in the 150-mg group. Relapse occurred in four 75-mg patients and in two 150-mg recipients, all within 4 weeks of treatment initiation. All patients who experienced virologic failure had genotype 1a; no other characteristics at baseline were associated with breakthrough.

Treatment was well tolerated in both groups. No patients discontinued treatment because of treatment-related serious adverse events, and symptoms while on treatment were mild or moderate in all but one patient who developed an AST elevation of grade 3-4 that later normalized, and one cirrhotic patient who experienced an elevation in bilirubin.

“This looks like a fairly good regimen: It’s a 12-week course of therapy, interferon-free, ribavirin-free, all-oral, three DAAs, and achieves an SVR12 in over 90% of treated patients,” presenter Gregory T. Everson, MD,University of Colorado, Denver, said. “And, in this study, this was achieved despite a high prevalence of genotype 1a subtype, advanced fibrosis, cirrhosis and a predominance of non-CC IL28B genotype. … These results support phase 3 trials with a twice-daily, fixed-dose combination of this regimen at the 75-mg dose of [BMS-791325].”

Disclosure: The researchers report numerous financial disclosures.

For more information:

Everson GT. LB-1: Late-Breaking Abstract Session: Phase 2b Study of the Interferon-free and Ribavirin-free Combination of Daclatasvir, Asunaprevir, and BMS-791325 for 12 Weeks in Treatment-Naive Patients with Chronic HCV Genotype 1 Infection. Presented at: The Liver Meeting 2013; Nov. 1-5, Washington.

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Also See: BMS Submits First All-Oral, Interferon-Free and Ribavirin-Free Treatment Regimen for Regulatory Review in Japan for Patients with Chronic Hepatitis C Infection

New HCV Drugs Offer Hope After Transplant

Meeting Coverage

Published: Nov 6, 2013

By Michael Smith, North American Correspondent, MedPage Today

WASHINGTON -- The advent of new all-oral regimens for hepatitis C (HCV) offers hope to patients who have undergone liver transplant and had the disease recur, a researcher said here.

Patients with hepatitis C who get a new liver universally have a recurrence of the disease in the new organ, according to Michael Charlton, MD, of the Mayo Clinic in Rochester.

Currently approved treatments have "poor tolerance, poor efficacy, severe adverse reactions, and significant interactions with immunosuppression medications," Charlton reported at the annual meeting of the American Association for the Study of Liver Diseases.

But preliminary results from an ongoing study using a novel medication, sofosbuvir, combined with the standard drug ribavirin suggest that those obstacles can be overcome, he said.

The study is "one of the most exciting papers presented today," commented Donald Jensen, MD, of the University of Chicago, who was not involved in the study but who moderated the session at which it was presented.

"It's data where we had poor treatment before this," he told MedPage Today, "and to get 80% cure rates in those patients is incredibly impressive."

He cautioned that the study is small and the results are still preliminary. But with approval of sofosbuvir expected within several weeks, "that's a very impactful study."

Charlton and colleagues are studying 40 patients -- more than 6 months and less than 150 months after transplant -- whose viral infection has recurred.

Most of the patients have high viral loads, genotype 1 HCV, unfavorable genetic variants, and either bridging fibrosis or cirrhosis.

They have been treated for 12 weeks with 400 mg daily of sofosbuvir and escalating doses of ribavirin, adjusted to keep hemoglobin levels as high as possible.

For this analysis, Charlton said, he had data on 39 patients who had completed treatment; all had undetectable virus at the end of therapy.

The primary endpoint of the study is the undetectable virus 12 weeks after the end of treatment (SVR12 ). So far, Charlton has data on 35 patients who had completed 4 weeks of follow-up after therapy.

Of those, 27 (77%) still had undetectable virus or SVR4.

There has been no apparent effect of sofosbuvir on immunosuppressive medications, Charlton reported.

As expected, the ribavirin effect on hemoglobin was marked. Eight of the four patients received epoetin, blood products, or both to compensate and 11 of the 40 had a reduction in ribavirin dose.

There have been six serious adverse events, but all were judged unrelated to the study drugs. Two patients stopped treatment because of adverse events, but there were no deaths, graft losses, or incidents of rejection.

More than a quarter of the patients had grades 3 or 4 lab abnormalities, but they were the type usually associated with ribavirin, including lymphocytopenia and low hemoglobin.

Taken overall, Charlton concluded, the drug combination is safe, well tolerated, and offers a "potential all-oral therapy for treatment of HCV infection following liver transplantation."

On the other hand, a European researcher confirmed that treatment with the current standard of care -- while better than in past years -- remains difficult to deliver and yields poor results.

Current therapy includes pegylated interferon and ribavirin, along with one of two recently approved protease inhibitors, telaprevir and boceprevir, noted Audrey Coilly, MD, of Hôpital Paul Brousse in Villejuif, France, who present results from a separate study.

But in a cohort of 79 recently transplanted HCV-positive patients, the treatment led to SVR12rates of 41% in patients getting telaprevir and in 51% of those on boceprevir, Coilly reported. And those rates were not sustained through 24 weeks -- the SVR24 rates were 27% and 47%, respectively.

A key finding, she said, was that 48% of boceprevir patients stopped treatment early, as did 61% of telaprevir patients.

Charlton reported no conflicts of interest. Coilly reported relationships with Gilead, Bristol Myers Squibb (BMS), Roche, and Novartis.

Their respective co-authors reported various relationships with multiple companies including, but not limited to, Roche, Gilead Sciences, Novartis, Boehringer Ingelheim, Merck, BMS, Janssen, Vertex, Pfizer, Medtronics, Schering-Plough, and Astellas.

Primary source: American Association for the Study of Liver Diseases
Source reference: Charlton M, et al "Sofosbuvir and ribavirin for the treatment of established recurrent Hepatitis C infection after liver transplantation: Preliminary results of a prospective, multicenter study" AASLD 2013; Abstract LB-2.

Additional source: American Association for the Study of Liver Diseases
Source reference:Coilly, A, et al "Sustained virological response after protease inhibitor-based therapy For Hepatitis C recurrence after liver transplantation: A multicentric European experience" AASLD 2013; Abstract 216.

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Also See: Gilead Announces Phase 2 Results for Sofosbuvir-Based Regimens in Hepatitis C Patients Before and After Liver Transplantation

ECHO model cost-effective for HCV

11/06/13

By: ALICIA AULT, Family Practice News Digital Network

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Alicia Ault/IMNG Medical Media
Dr. John B. Wong

WASHINGTON – Using the ECHO model of primary care to treat hepatitis C is cost saving in 35% of patients and very cost effective overall, according to a retrospective analysis presented by Dr. John B. Wong, at the annual meeting of the American Association for the Study of Liver Diseases.

Project ECHO (Extension for Community Healthcare Outcomes) was begun at the University of New Mexico, Albuquerque, and has been adopted by the Veterans Affairs department, among other organizations, as a means of extending primary care to those who might not otherwise have access.

This is not about the antiviral treatment, it’s about the engagement of primary care physicians, to train them, educate them, and help them take care of patients with hepatitis C," said Dr. Wong, chief of the division of clinical decision making at Tufts Medical Center, Boston. "It’s about increasing access," he added.

Dr. Wong presented the results of a cost-effectiveness analysis he and his Tufts colleagues conducted on a study of ECHO’s effectiveness in treating HCV, published in the New England Journal of Medicine in 2011 (N. Engl. J. Med. 2011;364:2199-207).

That prospective cohort study evaluated ECHO in the HCV treatment of 261 patients at 16 community sites and 5 prisons.

Dr. Wong and his colleagues updated the data, using information from the United Network for Organ Sharing; the Surveillance, Epidemiology and End Results Program; and life tables from the Centers for Disease Control and Prevention. They also used the previously established and validated Markov cohort simulation model to compare ECHO to no antiviral therapy for each of the 261 patients.

Costs taken into account included expenses for drugs, physician visits, lab tests, adverse events, HCV disease complications, and multidisciplinary ECHO personnel (physician, pharmacist, psychiatrist, nurse manager, coordinator, and user support analyst).

Dr. Wong said that the researchers also performed an analysis of the cost of antiviral treatment if patients traveled to the academic center to receive care instead of having ECHO come to them. Travel costs included mileage, patient time, and guard costs for prisoners. The investigators used quality-of-life adjustments to account for antiviral treatment and disease-related morbidity, and discounted costs and effectiveness at 3% a year.

They calculated that ECHO led to a 63% reduction in lifetime cirrhosis when compared with no antiviral therapy. Hepatocellular carcinoma declined by 45% and liver death by 46%. There was a 4.4-year gain in life expectancy overall, and a 5.5-year gain in quality-adjusted life expectancy.

For 42% of the 261 patients, the incremental effectiveness did not outweigh the cost – and the opportunity cost – of taking an antiviral, said Dr. Wong. In another 23% of patients, the antiviral therapy extended life, but in the end, when the costs of the disease and the antivirals were added in, there was an extra cost associated with the therapy.

But in 35% of the patients, there was an extension of life – as much as 8 additional years – and a reduction in cost of treatment, as much as $40,000.

he incremental cost-effectiveness ratio – a formula calculated by dividing the additional cost by the additional benefit – for ECHO is $3,700, Dr. Wong said. The World Health Organization considers anything less than the per capita gross domestic product of a country to be "very cost effective," and anything less than three times that per capita number to be "cost effective," he said. He noted that the mean GDP in the United States is $50,000, putting the ECHO intervention well within the WHO’s range for very cost effective.

The gains were even greater for patients living in correctional institutions, with an incremental cost-effectiveness ratio of $1,400.

The study is limited by the fact that it is a computer simulation, and some travel data were missing, said Dr. Wong.

Additional trials are needed to confirm the results, he said.

The University of New Mexico recently started an institute to spread the ECHO model.

Dr. Wong reported no conflicts of interest.

aault@frontlinemedcom.com
On Twitter @aliciaault

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Hep C will be eradicated starting in weeks

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Photo: wiki public domain

WASHINGTON, November 5, 2013 — Dr. Mitchell Shiffman of Bon Secours Liver Institute of Virginia has declared “There is no doubt we are on the verge of wiping out Hepatitis C”.

A happy Dr. Arthur Rubens entered a clinical trial to test a new pill against Hep C saying, “Taking it was a piece of cake” and after 90 days of treatment, the virus was declared cleared from his body after years of infection.

Hep C kills more Americans than AIDS and is the leading cause of liver transplants. The seemingly successful effort to eradicate it will potentially see the first viral epidemic wiped out sans a vaccine.

Starting in several weeks and continuing over the next several years, new drugs will be forthcoming to end Hep-C with a once-a-day pill without the multiple injections now required along with horrific side effects. The rate of cure will be substantially increased over current figures of 70 percent.

The drawbacks are the $60-$100,000 cost for a course of treatment and the possibility of many folks turning out to get the treatment who may never have so much as a hiccup from carrying the Hep C virus. Often those who are infected have no symptoms. If carriers appeal to medical insurance to cover the costs of the new treatmens, premiums are likely to increase for everyone.

Currently, about three to four million Americans have Hep C and the estimates of worldwide infection are about 150 million. These figures represent about three to five times the number of those infected with H.I.V.

The number of newly infected, about 17,000 annually, is a significant reduction from the 200,000 newly infected annually in the 1980’s. Health care officials attribute the slowing numbers to public education of the virus.

As with H.I.V., Hep C is known to be spread from drug abuse with needles, blood transfusions and sexual activity. The difference in treatment is that H.I.V. has a latent reservoir in the body and a victim must continue on medication for life to stop the virus from returning.

With Hep C, there is no reservoir so the virus can be destroyed. However, even with this, there is an increased risk of liver cancer and cirrhosis, particularly if scarring of the liver is pronounced.

However, Hep C expert Charles Rice at the Rockefeller University warns that new medications may have more side effects than currently noted. Rice notes, “We may be in for some surprises still,” and says that more clinical experience will reveal more information.

The Food and Drug Administration (FDA) is set to approve a new Hep-C drug, sofosbuvir, by December 8. This drug inhibits the virus’s polymerase enzyme that builds new genomes from RNA to allow viral replication. The new drug appears like the RNA building block but once adapted into the RNA chain, the virus cannot reproduce itself.

Current treatment for Hep C involves numerous rounds of painful injections and suffering side effects, which discourages those who spread the disease from seeking treatment. Those same individuals may be more likely to seek treatment if it involves taking pills, without the pain and side effects. This will not only provide relief for sufferers, but will also help reduce the spread of the disease as carriers receive treatment.

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NEJM Journal Watch

HIV and ID Observations

An ongoing dialogue on HIV/AIDS, infectious diseases, all matters medical, and some not so medical.

November 5th, 2013

Imagine for a moment the ideal medical future … there’s a vaccine that prevents the common cold … colon cancer screening no longer requires that horrendous “prep” … electronic medical records are easily accessible, intuitive, secure, and all communicate effortlessly with one another … your doctor’s office has an actual person who answers the phone instead of a pre-recorded list of “menu options” … and hepatitis C is cured with one pill a day taken for 8 weeks.

Not sure about the timeline for the first four, but based on this study of sofosbuvir and ledipasvir just published in the Lancet, the hepatitis C outcome is right around the corner:

In cohort A, SVR12 [no detectable virus 12 weeks after stopping treatment] was achieved by 19 (95%) of 20 patients (95% CI 75–100) in group 1, by 21 (100%) of 21 patients (84–100) in group 2, and by 18 (95%) of 19 patients (74–100) in group 3. In cohort B, SVR12 was achieved by 18 (95%) of 19 patients (74–100) in group 4 and by all 21 (100%) of 21 patients (84–100) in group 5 … These findings suggest that the fixed-dose combination of sofosbuvir-ledipasvir alone or with ribavirin has the potential to cure most patients with genotype-1 HCV, irrespective of treatment history or the presence of compensated cirrhosis.

You’ll note that the “groups” were pretty small, and that only one of them — group 1 — actually got just the one-pill sofosbuvir/ledipasvir combination for 8 weeks, but regardless, these are pretty spectacular results. Even the most “complex” treatment group in this study received sofosbuvir/ledipasvir plus ribavirin for only 12 weeks, which is light years from the complexity of our current interferon-based therapies. Light years better, of course.

And since sofosbuvir has already been reviewed by the FDA advisory panel, we should be getting at least this drug by December 2013 at the latest; the combination pill with ledipasvir could be available some time next next year (according to this article in the New York Times), and several other investigational HCV drugs will likely be approved soon as well (simeprevir this year too).

But calm down already. Take a deep breath. It’s a small Phase 2 study. Shouldn’t we be more cautious? Shouldn’t we avoid wildly overstating the importance of this particular treatment approach? Of course, that’s the prudent thing to do.

But can people with HCV and their treaters be ecstatic about these results anyway? You betcha.

Source

Also See: Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin in treatment-naive and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): an open-label, randomised, phase 2 trial

VIDEO: HCV Pathogenesis - The Liver Meeting 2013

WebsEdgeHealth

Published on Nov 4, 2013

Bruce Bacon, MD, Co-Director, Liver Center, Saint Louis University & Jordan Feld, MD, Toronto Western Hospital Liver Center, talks to AASLD TV about why amid all of the excitement surrounding the new therapeutics coming out for Hepatitis C, it's good to revisit the pathogenesis of the disease.

Source

WebsEdgeHealth

Published on Nov 4, 2013

Nancy Reau, MD, Associate Professor, University of Chicago Medical Center, talks to AASLD TV about why all of the potential therapies for Hepatitis C are coming out now and what potential challenges doctors may have in incorporating these treatments into their practice.

Source

11/01.13

By: TARA HAELLE, IMNG Medical News

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Lynda Banzi/IMNG Medical Media

According to two recent studies, consuming coffee of any kind may reduce the risk of the most common liver cancer by as much as 50 percent.

Drinking tea or caffeinated or decaf coffee is unlikely to influence a person’s risk for pancreatic cancer, but consuming coffee of any kind may reduce the risk of the most common liver cancer by as much as 50% (depending on amount consumed), according to two recent studies in Clinical Gastroenterology and Hepatology.

In the pancreatic cancer study, Dr. Nirmala Bhoo-Pathy of University Medical Center Utrecht, the Netherlands, and her colleagues reported, "Our results strengthen the conclusion made by the World Cancer Research Fund and the American Institute of Cancer Research that there is little evidence to support a causal relation between coffee and risk of pancreatic cancer (Clin. Gastroenterol. Hepatol. 2013 [doi:10.1016/j.cgh.2013.05.029]).

Meanwhile, a 16-study meta-analysis of coffee intake and risk for hepatocellular carcinoma, which accounts for more than 90% of worldwide liver cancers, revealed a 40% decreased risk (relative risk, 0.60; 95% confidence interval: 0.50-0.71) for any coffee consumption vs. no consumption. Yet Dr. Francesca Bravi of Università degli Studi di Milano and her colleagues reported that their findings could not establish a causal relationship between coffee drinking and hepatocellular carcinoma (Clin. Gastroenterol. Hepatol. 2013 [doi:10.1016/j.cgh.2013.04.039]).

Even such a causal relationship may have limited clinical significance, however, considering that more than 90% of primary liver cancers worldwide can theoretically be prevented through hepatitis B vaccination, control of hepatitis C transmission, and reduction of alcohol consumption, Dr. Bravi’s team wrote.

In the first study, Dr. Bhoo-Pathy’s investigation involved inspection of 865 first incidences of pancreatic cancers reported in a cohort of 477,312 men and women from 10 European countries tracked prospectively over a mean 11.6 years of follow-up. The participants in the EPIC (European Prospective Investigation Into Nutrition and Cancer) cohort completed a dietary questionnaire at baseline in 1992, then calibrated with a 24-hour dietary recall by the final follow-up in 2000.

The 23 participating centers were in Denmark, France, Germany, Greece, Italy, the Netherlands, Norway, Spain, Sweden, and the United Kingdom, and median coffee intake across these ranged from 92 mL/day in Italy to 900 mL/day in Denmark. Among the participants with all information on coffee type intake (n = 269,593), half drank only caffeinated coffee (50%), 4% drank only decaf, a third (34%) drank both, and 12% drank no coffee. Two-thirds (66%) of the total cohort drank tea of any kind (caffeinated, green, or herbal).

Neither total intake of coffee (hazard ratio, 1.03; 95% CI: 0.83-1.27 for high vs. low intake) nor consumption of decaffeinated coffee (HR, 1.12; 95% CI: 0.76-1.63) – reported as cups drunk per day, week, or month and then converted to daily milliliters – showed a significant change in pancreatic cancer risk. Tea consumption of any kind similarly had no impact on risk (HR, 1.22; 95% CI: 0.95-1.56). These risks did not change after accounting for a range of confounders nor when analysis was confined to the 608 (70.3%) cancers that were microscopically confirmed.

Confounders included sex, clinic/center, age at diagnosis, height, weight, physical activity, smoking status, diabetes history, education level, and energy intake, including red meat, processed meat, alcohol, soft drink, tea (for coffee analysis), coffee (for tea analysis), and fruit and vegetable intake.

A comparison of moderately low and low caffeinated coffee intake initially revealed a modest increased risk for moderately low consumption (HR, 1.33; 95% CI: 1.02-1.74) that dropped below statistical significance when only microscopically confirmed pancreatic cancer cases were analyzed. Additionally, no dose-response effect was noted among any of the findings for pancreatic cancer risk.

Yet a dose-response effect was seen in Dr. Bravi’s study investigating coffee consumption and hepatocellular carcinoma risk. Her team’s update of a 2007 meta-analysis included an additional four cohort and two case-control studies, for a total of eight cohort and eight case-control studies from 14 English-language articles included in PubMed/MEDLINE between 1966 and September 2012.

When broken down by study type, the 40% overall risk reduction for any coffee consumption found among 3,153 hepatocellular carcinoma cases split into a 44% reduction in the case-control studies (RR, 0.56; 95% CI: 0.42-0.75) and a 36% reduction in the cohort studies (RR, 0.64; 95% CI: 0.52-0.78).

The dose-response relationship was seen in separate comparisons of low and high coffee consumption with no coffee consumption, using three cups a day as the cutoff in nine papers and one cup a day in five papers. Low coffee consumption reduced hepatocellular carcinoma risk by 28% (RR, 0.72; 95% CI: 0.61-0.84) while high consumption reduced it by 56% (RR, 0.44; 95% CI: 0.77-0.84).

Each additional cup of coffee per day resulted in a 20% risk reduction (RR, 0.80; 95% CI: 0.77-0.84). This split into a 23% risk reduction in the case-control studies (RR, 0.77; 95% CI: 0.71-0.83) and a 17% risk reduction in the cohort studies (RR, 0.83; 95% CI: 0.78-0.88). A temporal analysis of risk reduction for any coffee consumption showed an increase from 20% risk reduction in 2000 (RR, 0.8; 95% CI: 0.50-1.29) to 41% in 2007 (RR, 0.59; 95% CI: 0.48-0.72), which has remained stable at about 40% the past several years.

Accounting for the most [significant] risk factors for liver cancer had little effect on the risk ratios. These factors included hepatitis B and C infections, cirrhosis, and other liver diseases, socioeconomic status, alcohol consumption, and smoking.

Dr. Bravi’s team suggested that the risk reduction effect could be a real, causal effect arising from antioxidants and other minerals in coffee that may inhibit liver carcinogenesis or from the inverse association between coffee and cirrhosis or coffee and diabetes, both conditions known risk factors for liver cancer. Or, the effect could result, at least in part, from reduced consumption of coffee among patients with cirrhosis or other liver disease.

"Thus, a reduction of coffee consumption in unhealthy subjects cannot be ruled out, although the inverse relation between coffee and liver cancer also was present in subjects with no history of hepatitis/liver disease," the researchers wrote. Yet, they also noted the potentially limited utility of coffee risk reduction given the greater impact on reducing liver cancer risk from hepatitis B vaccination, prevention of hepatitis C, and reduction of alcoholic drinking.

The pancreatic cancer study was funded by the European Commission and the International Agency for Research on Cancer, with a long list of additional societies, foundations, and educational institutions supporting the individual national cohorts. The hepatocellular carcinoma study was funded by a grant from the Associazione Italiana per la Ricerca sul Cancro. The authors in both studies reported no disclosures.

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