September 17, 2013

Journal of Hepatology
Volume 59, Issue 4 , Pages 885-888, October 2013

Tarik Asselah

Received 11 March 2013; received in revised form 15 May 2013; accepted 15 May 2013. published online 28 May 2013.

Abbreviations: DAA, direct-acting antivirals, PegIFN, pegylated interferon, SVR, sustained virological response, eRVR, extended rapid virological response, RVR, rapid virologic response

Keywords: Direct-acting antivirals, Sustained virological response, Chronic hepatitis C, NS5A inhibitors, Safety, Resistance

COMMENTARY ON:

Exploratory study of oral combination antiviral therapy for hepatitis C. Poordad F, Lawitz E, Kowdley KV, Cohen DE, Podsadecki T, Siggelkow S, Heckaman M, Larsen L, Menon R, Koev G, Tripathi R, Pilot-Matias T, Bernstein B. N Engl J Med. 2013 Jan 3;368(1):45-53. Copyright © 2012 Massachusetts Medical Society. Abstract reprinted with permission from Massachusetts Medical Society. http://www.ncbi.nlm.nih.gov/pubmed/23281975

Abstract. Background: There is a need for interferon-free treatment regimens for hepatitis C virus (HCV) infection. The goal of this study was to evaluate ABT-450, a potent HCV NS3 protease inhibitor, combined with low-dose ritonavir (ABT-450/r), in addition to ABT-333, a nonnucleoside NS5B polymerase inhibitor, and ribavirin, for the treatment of HCV infection.

Methods: We conducted a 12-week, phase 2a, open-label study involving patients who had HCV genotype 1 infection without cirrhosis. All patients received ABT-333 (400mg twice daily) and ribavirin (1000 to 1200mg per day) and one of two daily doses of ABT-450/r. Groups 1 and 2 included previously untreated patients; group 1 received 250mg of ABT-450 and 100mg of ritonavir, and group 2 received 150mg and 100mg, respectively. Group 3, which included patients who had had a null or partial response to previous therapy with peginterferon and ribavirin, received daily doses of 150mg of ABT-450 and 100mg of ritonavir. The primary end point was an undetectable level of HCV RNA from week 4 through week 12 (extended rapid virologic response).

Results: A total of 17 of the 19 patients in group 1 (89%) and 11 of the 14 in group 2 (79%) had an extended rapid virologic response; a sustained virologic response 12 weeks after the end of treatment was achieved in 95% and 93% of the patients, respectively. In group 3, 10 of 17 patients (59%) had an extended rapid virologic response, and 8 (47%) had a sustained virologic response 12 weeks after therapy; 6 patients had virologic breakthrough, and 3 had a relapse. Adverse events included abnormalities in liver-function tests, fatigue, nausea, headache, dizziness, insomnia, pruritus, rash, and vomiting.

Conclusions: This preliminary study suggests that 12 weeks of therapy with a combination of a protease inhibitor, a non-nucleoside polymerase inhibitor, and ribavirin may be effective for treatment of HCV genotype 1 infection. (Funded by Abbott; ClinicalTrials.gov number, NCT01306617.)

Introduction

Two direct-acting antivirals (DAAs), telaprevir and boceprevir, are given in combination with pegylated interferon (PegIFN) and ribavirin to genotype 1 HCV infected patients. PegIFN has several side effects and many patients are not eligible or have failed this treatment. Therefore, there is a need to develop an IFN-free regimen. Ideally, the future IFN-free regimen should have a high efficacy, favorable safety profile, and high barrier to resistance [1]. This article is discussing the impressive data from the IFN-free trial with ABT-450 based regimen [2], [3].

ABT-450 is an inhibitor of NS3/4A protease that is metabolized by cytochrome P450 isoform 3A (CYP3A). ABT-450 is co-administered with ritonavir (ABT-450/r), a CYP3A inhibitor, to enhance ABT-450 exposure. ABT-450/r is dosed once daily. ABT-267 is an NS5A inhibitor that is dosed once daily. ABT-333 is an NS5B polymerase non-nucleoside inhibitor dosed twice daily.

ABT-450 boosted with ritonavir (ABTr), in addition to ABT-333, and ribavirin for HCV genotype 1 infected patients (pilot and co-pilot studies)

Study design 

Impressive results were reported recently from a phase 2a multicenter open-label study [2]. Groups 1 (n=19) and 2 (n=14) included naïve patients, and group 3 (n=17) included null (n=7) or partial responders (n=10) to previous therapy (Fig. 1A). All patients received triple therapy with ABT-450r, ABT-333, and ribavirin, for 12 weeks.

PIIS0168827813003516_gr1_lrg

Fig. 1. Trial designs and results of studies with ABT-333 based regimen. (A) Phase 2a, multicenter, open-label, trial design [2]. All patients received ABT-333 (400mg twice daily) and ribavirin (1000–1200mg per day) and one of two daily doses of ABT-450/r. Groups 1 and 2 included previously untreated patients; group 1 received 250mg of ABT-450 and 100mg of ritonavir, and group 2 received 150mg and 100mg, respectively. Group 3, which included patients who had had a null (n=7) or partial response (n=10) to previous therapy with PegIFN/ribavirin, received daily doses of 150mg of ABT-450 and 100mg of ritonavir. ABT-450, NS3 protease inhibitor, boosted with ritonavir (ABT-450/r); ABT-333, non-nucleoside NS5B polymerase inhibitor. (B) Phase 2a, multicenter, open-label, trial results [2]. A total of 17 of the 19 patients in group 1 (89%) and 11 of the 14 in group 2 (79%) had an extended rapid virologic response; an SVR 12weeks after the end of treatment was achieved in 95% and 93% of the patients, respectively. In group 3, 10 of 17 patients (59%) had an extended rapid virologic response, and 8 (47%) had an SVR 12weeks after therapy; 6 patients had virologic breakthrough, and 3 had a relapse. HCV RNA<LDQTD or TND (<25IU/ml); eRVR=extended rapid virological response defined as undetectable HCV RNA from week 4 through week 12.

End points 

The primary end point was the percentage of patients with undetectable HCV-RNA from week 4 through week 12 (extended rapid virologic response, eRVR). Secondary end points included patients with HCV-RNA below 25IU/ml at week 4 (rapid virologic response, RVR), at week 12, and 12weeks after the end of treatment (sustained virologic response (SVR)). SVR12 has been demonstrated to be as relevant as SVR24 under PegIFN/ribavirin [4]. COBAS TaqMan HCV Test, version 2.0 was used, with a lower limit of quantitation of 25IU/ml and a lower limit of detection of 15IU/ml.

Efficacy in naïve patients 

17/19 patients in group 1 and 11/14 in group 2 had an eRVR (Fig. 1B). None of the patients in group 1 or 2 had virologic breakthrough and none who completed treatment had a relapse; all patients who completed treatment had an SVR12. All 18 patients who completed treatment in group 1 had undetectable HCV RNA 48weeks after treatment. 2/13 patients who completed treatment in group 2 discontinued the study after week 12 of follow-up; the other 11 patients had undetectable HCV 48weeks after treatment.

Efficacy in patients with null or partial response to previous therapy 

6 patients had virologic breakthrough during treatment, including 1 who mistakenly took only 50mg of ABT-450 daily for the first 3weeks and who never had an HCV RNA lower than 25IU/ml. Ten patients had an eRVR. Three patients had a relapse 2weeks after treatment, and 8 had an SVR12. 3/7 patients with a null response and 5/10 with a partial response had SVR12. In most cases, virologic failure was associated with the emergence of variants with substitutions in both NS3 and NS5B, at positions known to confer resistance in vitro to ABT-450 and ABT-333, respectively.

Safety

No deaths or serious adverse events occurred. One patient in group 1 discontinued drugs owing to aminotransferases increase at week 2. The elevated aminotransferase levels were not associated with an increased bilirubin level and improved after treatment. The most frequent events were fatigue, nausea, headache, dizziness, insomnia, pruritus, rash, and vomiting. Most events were mild. Four adverse events were classified as severe: fatigue, pain, vomiting, and hyperbilirubinemia. None of these events led to drug discontinuation.

ABT-450/r, ABT-267, ABT-333 and ribavirin (Aviator study) 

The Aviator phase 2b study assesses the safety and efficacy of ABT-450/r, ABT-267 (NS5A inhibitor), ABT-333, and ribavirin in non-cirrhotic naïve patients and prior PegIFN/ribavirin null-responders for 8, 12 or 24weeks (Fig. 2A) [3]. Results are summarized in Fig. 2B. For the 12-week triple-DAA regimen with ribavirin being studied in phase 3 trials: 96% of treatment-naive patients achieved SVR; and 93% of prior null responders achieved SVR. Comparable high response rates were obtained in the 12- or 24-week arms, supporting a 12-week treatment duration. Treatment was well tolerated. Four of 448 patients in the 8- and 12-week arms discontinued treatment because of adverse events. The most common adverse events were fatigue and headache.

PIIS0168827813003516_gr2_lrg

Fig. 2. Aviator study. (A) Trial design [3]. This phase 2b study assesses the safety and efficacy of ABT-450/r (dosed 100/100mg to 200/100mg QD), ABT-267 (25mg QD), ABT-333 (400mg BID), and ribavirin in non-cirrhotic treatment-naïve patients and prior PegIFN/ribavirin null responders for 8, 12 or 24weeks. ABT-450, NS3 protease inhibitor, boosted with ritonavir (ABT-450/r); ABT-267, NS5A inhibitor; ABT-333, non-nucleoside NS5B polymerase inhibitor. (B) Results from the Aviator study [3]. SVR in treatment-naїve genotype 1 (GT1) patients and in GT1 null responder patients.

Discussion: what have we learned? 

First, for naive genotype 1 patients without cirrhosis («easy-to-cure patients»), this preliminary study suggests that the all-oral combination of 2 DAAs (ABT-450/r, ABT-333), and ribavirin for 12weeks is associated with a high SVR rate. According to subtype, no virologic failures occurred among the 26 genotype 1a naïve patients.

Second, this regimen (ABT-450/r, ABT-333, and ribavirin) is less effective in null or partial responders to previous therapy («difficult-to-cure patients»). Extending the treatment duration beyond 12weeks may not be an option since most of the virologic failures occurred during treatment. We do not really understand why treatments including DAAs are less effective in treatment-experienced patients when compared to naïve patients, even in the absence of IFN therapy. Innate immunity may still have a role in HCV clearance with these DAAs [5]. For previous non-responders, more potent combination with different compounds may be needed. The combination of several DAAs (ABT-450/r, ABT-267, ABT-333, and ribavirin) in non-cirrhotic prior null-responders provides excellent preliminary results. Moreover, PegIFN may remain an option in previous non-responders (or as a rescue therapy), since a high SVR rate was achieved when two DAAs were combined with PegIFN/ribavirin [6].

Third, we will have to wait for more data, with a larger number of patients, including difficult-to-cure patients with cirrhosis and previous non-response. Of course, phase 3 studies will provide more information about safety, effectiveness, and drug-drug interactions, especially when several new drugs are developed in the same regimen (and ABT-450 is boosted with ritonavir).

Conclusions

Finally, ABT-450-based regimen showed impressive results. It is unclear whether ribavirin will remain an important agent. For easy-to-cure patients, “genotype 1b with mild disease”, ribavirin may be not useful. For difficult-to-cure patients, “cirrhosis with prior non-response”, an intensive regimen may be necessary.

The phase 3 program is ongoing. The DAAs in the studies include ABT-450/r (protease inhibitor and ritonavir), ABT-267 (NS5A inhibitor) and ABT-333 (non-nucleoside polymerase inhibitor). Treatment duration will be 12weeks in non-cirrhotic patients and 12 or 24weeks in cirrhotic patients. All patients will be followed for 48weeks post-treatment. Co-formulated tablets of ABT-450/r and ABT-267 will be used in phase 3 trials. (http://www.clinicaltrials.gov.)

There is a realistic hope for an oral regimen against HCV since several DAA combinations have reported interesting preliminary results (increased SVR, low resistance and a preliminary good safety profile) [7], [8], [9]. We have to take into account this important revolution, but remain cautious and await larger phase 3 data, especially regarding safety and drug-drug interactions. Finally, we wish a nice flight to Aviator, and we hope that in the near future an IFN-free regimen will be available for patients with HCV infection.

Conflict of interest 

Tarik Asselah is a speaker and investigator for BMS, Boehringer-Ingelheim, Tibotec, Janssen, Gilead, Roche, and Merck.

References 

Source

Journal of Hepatology
Volume 59, Issue 4 , Pages 675-683, October 2013

Thierry Poynard, Joseph Moussalli, Mona Munteanu, Dominique Thabut, Pascal Lebray, Marika Rudler, Yen Ngo, Vincent Thibault, Helmi Mkada, Frederic Charlotte, Françoise Imbert Bismut, Olivier Deckmyn, Yves Benhamou, Marc Antoine Valantin, Vlad Ratziu, Christine Katlama, FibroFrance-GHPS group

Received 31 March 2013; received in revised form 29 April 2013; accepted 8 May 2013. published online 28 May 2013.

Abstract

Background & Aims

Chronic hepatitis C is both a virologic and fibrotic disease and complications can occur in patients with sustained virologic response (SVR) with residual fibrosis. Due to the limitations of repeated biopsies, no studies have assessed the dynamic of fibrosis before and after treatment. Using biopsy as reference, FibroTest™ has been validated as a biomarker of fibrosis progression and regression, with similar prognostic values. The aim was to estimate the impact of SVR on the dynamic of fibrosis presumed by FibroTest™.

Methods

In a prospective cohort, the main end point was the 10-year regression rate of fibrosis, defined as a minimum 0.20 decrease in FibroTest™, equivalent to one METAVIR stage.

Results

A total of 933 patients with both repeated FibroTest™ and transient elastography were included. At 10years, among the 415 patients with baseline advanced fibrosis, 49% (95% CI 33–64%) of the 108 SVR had a regression, which was greater than in the 219 non-responders [23% (14–33%; p<0.001 vs. SVR)] and not lower than in the 88 non-treated [45% (10–80%; p=0.39 vs. SVR)] patients. In all 171 SVR, cirrhosis regressed in 24/43 patients, but 15 new cirrhosis cases occurred out of 128 patients, that is only a net reduction of 5.3% [(24–15)=9/171); (2.4–9.8%)]. Four cases of primary liver cancer occurred in SVR [4.6% (0–9.8)], and 13 in non-responders [5.6% (1.5–9.8); p=0.07].

Conclusions

In patients with chronic hepatitis C, and as presumed by FibroTest™, virological cure was associated with slow regression of fibrosis 10years later, a disappointing 5% decrease in cirrhosis cases, and a remaining 5% risk of primary liver cancer.

Keywords: Cirrhosis, FibroTest™, FibroSure, Elastography

PII: S0168-8278(13)00345-0

doi:10.1016/j.jhep.2013.05.015

© 2013 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.

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Provided by NATAP

53rd ICAAC Interscience Conference on
Antimicrobial Agents and Chemotherapy
September 10-13, 2013, Denver CO

53rd ICAAC, September 10-13, 2013, Denver

from Jules: SVR reduced risk for AIDS progression and serious liver-related events in non-advanced as well as in patients with advanced HCV disease, thus as the authors say all HIV+ patients should be treated for HCV quick without undue delay, delaying therapy risks progression of HIV & HCV, even for patients with non-advanced disease but of course mores for patients with advanced disease. With the expected availability of new HCV therapies later this year but with peg interferon, and in 2014 IFN-free regimens with 95-100% SVR rates in phase 2 are expected to become available, coinfected patients should be treated without undue delay. If you view the slides below on "Rates of Events" you will see progression to AIDS, liver decompensation, HCC, overall mortality & liver-related mortality is reduced by as much as 10-fold.

Mark Mascolini

Sustained virologic response (SVR) to interferon plus ribavirin (IFN/RBV) with nonadvanced or moderate fibrosis lowered the risk of mortality and liver-related progression in a large Spanish cohort of people with HIV/HCV coinfection [1]. The benefit was most pronounced in people with moderate (METAVIR F2) liver fibrosis.

Previous work established the benefits of eradicating HCV in people with advanced fibrosis or cirrhosis. But researchers working with the GESIDA 3606 Study Cohort observed that the clinical benefits of attaining SVR have not been established in people with less advanced fibrosis. They argued that this question is especially relevant for HIV/HCV-coinfected people. The GESIDA team conducted this retrospective analysis to assess the impact of IFN/RBV-induced SVR on mortality, liver-related events, and HIV progression in HIV/HCV-coinfected people with biopsy-proved nonadvanced liver fibrosis.

The study group consists of people with HIV and HCV who began IFN/RBV between January 2000 and January 2008 at 19 clinical centers across Spain. Baseline liver biopsies in all participants had a METAVIR score of F0, F1, or F2. Follow-up continued from the time IFN/RBV stopped until the last study visit, a second course of IFN/RBV, or death.

Among 695 people who met those criteria, 77 (11%) had a METAVIR score of F0, 290 (42%) had F1 fibrosis, 328 (47%) had F2 fibrosis, and 274 (39%) achieved SVR. Most people in the SVR and no-SVR groups (69% and 75%) were men, while CD4 counts averaged 562 and 536. The groups were similar in median age (39.8) and weight (68 kg), proportion with low educational level (62%), proportion of prior injection drug users (83%), and proportion with an undetectable HIV load (66%). The proportion of people with CDC category C disease was lower in the SVR group than in the no-SVR group (16% versus 22%, P < 0.05).

People who attained SVR included a lower proportion with HCV genotype 1 or 4 (44% versus 76%, P < 0.05) and thus a higher proportion with genotype 2 or 3 (56% versus 24%). The SVR group also included a lower proportion with a pretreatment HCV load at or above 500,000 IU/mL (62% versus 76%, P < 0.05) and a lower proportion who drank more than 50 g of alcohol daily (2% versus 6%, P < 0.05). METAVIR fibrosis scores did not differ significantly between people who attained SVR and those who did not.

Three variables predicted SVR: HCV genotype 2 or 3 (odds ratio [OR] 4.24, 95% confidence interval [CI] 2.91 to 6.19), pretreatment HCV load below 500,000 IU/mL (OR 1.88, 95% CI 1.27 to 2.78), and drinking less than 50 g of alcohol daily (OR 4.04, 95% CI 1.11 to 14.8).
Through 96 months of follow-up, cohort members who attained SVR had significantly lower Kaplan-Meier-estimated overall mortality (P = 0.010), liver-related mortality (P = 0.024), liver decompensation (P = 0.010), and liver-related events (which included liver-related death, liver decompensation, hepatocellular carcinoma, and liver transplantation) (P < 0.001).

Among people with an F2 METAVIR score, people who achieved SVR had significantly lower mortality (0.29 versus 1.07 per 100 person-year [py]), liver-related mortality (0.07 versus 0.53 per 100 py), AIDS incidence (0.14 versus 0.69 per 100 py), and liver decompensation rate (0.22 versus 1.31 per 100 py) (P < 0.05 for all differences) than people who did not attain SVR. An analysis focused on people with F2 fibrosis found that those attaining SVR had significantly lower mortality (0.16 versus 1.57 per 100 py), liver-related mortality (0.16 versus 1.05 per 100 py), and liver decompensation rate (0.16 versus 1.85 per 100 py) (P < 0.05 for all differences) than people who did not attain SVR. Among people with a METAVIR score of F0 or F1, these progression rates did not differ significantly between those who attained SVR and those who did not.

Cox regression analysis to determine risk of liver-related events according to METAVIR fibrosis stage adjusted for age, gender, history of injection drug use, CDC clinical category, CD4 count, HCV genotype, and HCV load. In this analysis people who attained SVR with F0 to F2 fibrosis or with F2 fibrosis had almost a 90% lower risk of progression, as indicated in the following list. The group with F0 or F1 fibrosis had about an 80% lower risk of progression, but this difference stopped short of statistical significance:

Progression risk with SVR versus no SVR:
METAVIR F0-F2: adjusted hazard ratio (aHR) 0.13, 95% CI 0.03 to 0.59, P = 0.008
METAVIR F2: aHR 0.11, 95% CI 0.01 to 0.86, P = 0.035
METAVIR F0-F1: aHR 0.21, 95% CI 0.02 to 1.94, P = 0.169

The GESIDA team concluded that "eradication of HCV in HIV/HCV-coinfected patients with nonadvanced liver fibrosis (F0 to F2), and, more specifically, with moderate stages of liver fibrosis (F2), is associated with a reduction in the risk of mortality and liver-related events." They argued that these findings "constitute a strong rationale for considering anti-HCV treatment in this population group, particularly treatment based on the newer and more effective direct antiviral agents."

ReferenceL

1. Berenguer J, Zamora FX, Díez C, et al. Hepatitis C eradication reduces liver decompensation, HIV progression, and death in HIV/HCV-coinfected patients with non-advanced liver fibrosis. 53rd ICAAC. September 10-13, 2013. Denver. Abstract H-1527.

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Hepatitis C Eradication Reduces Liver Decompensation, HIV progression, and Death in HIV/HCV-coinfected Patients with non-Advanced Liver Fibrosis

Continue here to view posters ……

Provided by Healio

September 17, 2013

Patients with hepatocellular carcinoma of smaller size experienced similar survival and safety outcomes from hepatic resection and radiofrequency ablation in a study presented at the International Liver Cancer Association Annual Conference in Washington, DC.

Researchers evaluated 659 patients who developed hepatocellular carcinoma (HCC) between 1999 and 2007. Patients included 289 who received percutaneous, ultrasound-guided radiofrequency ablation (RFA) while under general anesthesia, and 370 who underwent hepatic resection as initial curative therapy. All nodules were 5 cm in size or smaller.

“Whether RFA is a feasible alternative treatment for small HCC remains controversial,” the researchers wrote. “Thus, instead of a randomized controlled trial, we conducted a propensity analysis to compare the outcomes of RFA versus surgery.”

At 5 years after treatment, survival rates were 65% of RFA recipients and 68% of surgery recipients, while recurrence-free survival rates were 27% and 26%, respectively. The two methods did not differ significantly on Cox proportional hazards analysis, or on propensity analysis incorporating 146 propensity-score-matched pairs from each group. Investigators said patients with poor liver function were more likely to undergo RFA, while patients with highly malignant tumors were more likely undergo resection.

Bleeding into the abdominal cavity occurred in 0.3% of patients who received RFA. Death due to surgery-related complications occurred in 0.5% of resected patients.

“There was no difference in either overall or recurrence-free survival between patients undergoing RFA and those treated surgically,” the researchers concluded. “If appropriate patient selection criteria are applied, RFA under general anesthesia is a safe and effective treatment for small HCC.”

Disclosure: The researchers report no relevant financial disclosures

For more information:

Saito A. P-125: Radiofrequency Ablation Under General Anesthesia Versus Hepatic Resection for Hepatocellular Carcinoma. Presented at: The International Liver Cancer Association Annual Conference 2013; Sept. 13-15, Washington, DC.

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Coffee May Offer Real Benefits to the Liver

Provided by Clinical Care options

Mark S. Sulkowski, MD - 8/13/2013 More from this author

Mixed Realities of Alternative Therapies for Hepatitis
Approximately 50% of patients who have failed initial therapy for hepatitis C take some form of alternative or complementary therapy. In my practice, I’m frequently asked by these and other patients: “What can I do to help my liver?” Most have heard of, have taken, or are taking milk thistle, licorice root, ginseng, schisandra, and/or thymus extract—with milk thistle being the most common. Not all alternative therapies are created equal and there are few randomized controlled trials to guide clinicians seeking answers. For instance, the active ingredient in milk thistle, silymarin, has been evaluated and generally found to provide little or no clinical benefit to the liver. In fact, a recent study found that even at higher-than-usual doses, silymarin failed to reduce HCV RNA or ALT levels more than placebo.

There is, however, a growing body of research supporting a beverage I’d wager a majority of you have enjoyed today: coffee.

The Coffee Alternative
Curiously, patients who will spend up to $30 a day or more for milk thistle and its extracts or ingest unproven therapies of varying quality are skeptical about the idea that drinking coffee can actually be good for you. Real and perceived cardiovascular and other effects of coffee have led many patients to view coffee as “unhealthy.” But the reality is that coffee consumption has been linked to a number of potential benefits – lower risk of diabetes, dementia and, yes, liver disease. Coffee contains more than 1000 compounds; one or more of which is responsible for the benefit that has been linked to coffee intake on liver disease in patients with alcoholic and viral hepatitis. Benefits include decreases in markers of liver disease progression and reductions in the risk for fibrosis and hepatocellular carcinoma.

Epidemiologic studies have suggested that there is a cause and effect associated with coffee intake and its benefits on the liver. These findings are supported by the few randomized controlled trials available. In one study comparing patients infected with hepatitis C, those who drank 3 cups of coffee per day or more received the greatest benefit. In order to maximize the effects of the coffee some (but not all) studies suggest that caffeinated coffee may be better for the liver than decaffeinated coffee. However, it seems that caffeine itself does not appear to have a beneficial effect.

There is also an interesting conundrum. Not just any caffeinated beverage will do. For instance, studies evaluating the effect of green tea – popularly considered a “healthier” source of caffeine – have not shown the benefits associated with filtered, caffeinated coffee. This lack of benefit appears to be true for sources of caffeine other than green tea as well.

Lastly, coffee should ideally be prepared by filtration because filtering removes cafestol and kahweol, two substances found in coffee that may increase serum cholesterol.

Continue reading full article here …..

NIH-funded study suggests brain is hard-wired for chronic pain

For Immediate Release: Tuesday, September 17, 2013

Brain’s white matter may determine susceptibility to chronic pain

The structure of the brain may predict whether a person will suffer chronic low back pain, according to researchers who used brain scans. The results, published in the journal Pain, support the growing idea that the brain plays a critical role in chronic pain, a concept that may lead to changes in the way doctors treat patients. The research was supported by the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health.

“We may have found an anatomical marker for chronic pain in the brain,” said Vania Apkarian, Ph.D., a senior author of the study and professor of physiology at Northwestern University Feinberg School of Medicine in Chicago.

Chronic pain affects nearly 100 million Americans and costs the United States up to $635 billion per year to treat. According to the Institute of Medicine, an independent research organization, chronic pain affects a growing number of people.

A Map of Chronic Pain
Scientists used the structure of the brain’s white matter (green lines) to predict whether a subject would recover from low back pain. Red dots represent differences in white matter structure between subjects who recovered and who suffered chronic pain. Courtesy of Apkarian lab, Northwestern University Feinberg School of Medicine.

“Pain is becoming an enormous burden on the public. The U.S. government recently outlined steps to reduce the future burden of pain through broad-ranging efforts, including enhanced research,” said Linda Porter, Ph.D, the pain policy advisor at NINDS and a leader of NIH’s Pain Consortium. “This study is a good example of the kind of innovative research we hope will reduce chronic pain which affects a huge portion of the population.”

Low back pain represents about 28 percent of all causes of pain in the United States; about 23 percent of these patients suffer chronic, or long-term, low back pain.

Scientists have thought the cause of low back pain could be found at the site of injury. However, recent studies suggest that the brain may be more involved with chronic pain.

“Currently we know very little about why some patients suffer chronic low back pain,” said Debra Babcock, M.D., Ph.D., a program director at NINDS. “The earlier we detect pain will become chronic, the better we may be able to treat patients.”

Dr. Apkarian and his colleagues addressed this by scanning the brains of 46 people who had low back pain for about three months before coming to the hospital but who had not had any pain for at least a year before.

The researchers scanned the subjects’ brains and evaluated their pain with doctor’s examinations and questionnaires four times over a period of one year. About half of the subjects recovered at some time during the year; the other half had pain throughout, which the researchers categorized as persistent.

Previously, the Apkarian laboratory showed that the volume of grey matter in the brains of the same subjects who had persistent pain decreased over the same year. Grey matter describes the area of the brain where the central bodies and branched antennae, or dendrites, of nerve cells reside. They also showed that brain activity could be used to predict whether a subject recovered or experienced persistent pain.

In this study, the researchers used a scanning technique called diffusion tensor imaging (DTI) which measures the structure of white matter, the nerve cell wires, or axons, which connect brain cells in different parts of the brain. They found a consistent difference in white matter between the subjects who recovered and the subjects who experienced pain throughout the year.

“Our results suggest that the structure of a person’s brain may predispose one to chronic pain,” said Dr. Apkarian.

In agreement with this idea, the researchers also found that the white matter of subjects who had persistent pain looked similar to a third group of subjects known to suffer from chronic pain. In contrast, the white matter of the subjects who recovered looked similar to that of healthy control subjects.

To test this idea further, the researchers asked whether the white matter differences they saw during the initial brain scans predicted whether the subjects would recover or continue to experience pain. They found white matter brain scans predicted at least 80 percent of the outcomes.

“We were surprised how robust the results were and amazed at how well the brain scans predicted persistence of low back pain,” said Dr. Apkarian. “Prediction is the name of the game for treating chronic pain.”

The nucleus accumbens and the medial prefrontal cortex are two brain regions thought to be involved with pain. Further examination of the brain scans suggests that the white matter structure connecting these brains regions is different between the subjects who recovered and those who had persistent pain.

“Our results support the notion that certain brain networks are involved with chronic pain,” said Dr. Apkarian. “Understanding these networks will help us diagnose chronic pain better and develop more precise treatments.”

This study was supported by a grant from NINDS (NS35115) and an anonymous foundation.

NINDS is the nation’s leading funder of research on the brain and nervous system. The NINDS mission is to reduce the burden of neurological disease – a burden borne by every age group, by every segment of society, by people all over the world.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

NIH...Turning Discovery Into Health®

References

Mansour et al. “Brain white matter structural properties predict transition to chronic pain” Pain, 154, October 2013, DOI #: 10.1016/j.pain.2013.06.044

For more information about chronic pain, please visit:
http://www.ninds.nih.gov/disorders/chronic_pain/chronic_pain.htm

For more information about NIH’s Pain Consortium, please visit:
http://painconsortium.nih.gov

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The regulatory process in Japan for Simeprevir

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17-Sep-13 Stockholm, Sweden — Medivir AB (OMX: MVIR) On February 22, 2013 Janssen submitted a regulatory application to the Japanese Ministry of Health & Welfare authorities seeking approval for simeprevir, administered with pegylated interferon (Peg-IFN) and ribavirin (RBV) for the treatment of genotype 1 chronic hepatitis C.

As a part of the regulatory process there has been a closed meeting where simeprevir has been discussed by leading clinicians in Japan. The purpose of the meeting was to evaluate simeprevir and give guidance to the regulatory authorities.

The conclusions from this closed meeting are not officially known to us and Medivir will return with information when the regulatory process allows.

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

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

For more information about Medivir AB, please visit the Company’s website: www.medivir.com

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PR-Logo-Newswire

PRESS RELEASE September 17, 2013, 7:19 a.m. ET

- Patent valid until at least 2031 -

JERUSALEM, Sept. 17, 2013 /PRNewswire/ -- BioLineRx Ltd. (NASDAQ:BLRX) (TASE:BLRX), a biopharmaceutical development company, announced today that a Notice of Allowance has been issued by the United States Patent and Trademark Office (USPTO) for BL-8020, an orally available, interferon-free treatment for hepatitis C. The patent covers the use of BL-8020 for treating HCV-infected patients non-responsive to an anti-HCV therapy (patients who failed to achieve a sustained virologic response following treatment). The patent will be valid until at least 2031.

(Logo: http://photos.prnewswire.com/prnh/20130730/630769 )

"We are very pleased to have received a Notice of Allowance from the USPTO for the BL-8020 patent. This is an important milestone in the development of this promising drug candidate," stated Dr. Kinneret Savitsky, Chief Executive Officer of BioLineRx. "HCV induces a chronic infection in more than half of individuals infected with the disease and, depending on the virus genotype, as few as 60% completely recover. In addition, current standard-of-care treatments are lengthy and not well tolerated. As a result, there is a clear need for therapeutics that can increase the effectiveness of existing treatments, especially in patients who have already undergone treatment, but have failed to respond or have relapsed. Based on its pre-clinical results, unique mechanism of action and synergistic effect with other anti-HCV compounds, we are very hopeful that BL-8020 will enhance the effectiveness of other available hepatitis C treatments, thereby significantly improving hepatitis C care. We look forward to the partial results from the Phase 1/2 trial expected towards the beginning of 2014."

BioLineRx is currently conducting a Phase 1/2, open-label study at two sites in France to evaluate the efficacy, safety and tolerability of BL-8020 in patients infected with HCV. The study will include up to 32 HCV-infected patients of any genotype who have previously failed or relapsed following treatment with the standard-of-care. BL-8020 is a proprietary oral, fixed-dose combination treatment composed of Ribavirin and Hydroxychloroquine (HCQ). The primary endpoint of the study is to evaluate the effect of a 16-week combination therapy with Ribavirin and HCQ. The study is specifically designed to allow intra-subject analysis, in order to determine the extent to which HCQ enhances Ribavirin's antiviral activity.

About BL-8020

BL-8020 is a proprietary fixed-dose combination treatment composed of Ribavirin and Hydroxychloroquine (HCQ). Efficacy results in replicon assays, as well as in ex-vivo infected human liver samples, showed a time and dose-dependent inhibitory effect of BL-8020 on HCV replication and infectivity. In addition, a synergistic effect with other anti-HCV agents was observed in these models. This effect on other therapies is likely to increase their potency and reduce the numerous adverse effects often associated with these drugs by reducing their effective doses. BL-8020 targets the infected host cells and inhibits HCV induced autophagy in the host. This unique mechanism of action differentiates BL-8020 from other currently used anti-HCV agents in its potential pan genotypic activity and high genetic barrier to resistance (low susceptibility for drug-resistant mutations to be developed by the virus). BL-8020 was licensed under a worldwide, exclusive agreement from Genoscience, a French company focused on viral disease therapeutics. It was developed as an anti-viral therapy by Professor Philippe Halfon, Co-Founder and President of Genoscience and a world-renowned scientist for his work on HIV, HPV (human papilloma virus causing cervical cancer) and hepatitis.

About Hepatitis C

Hepatitis C infection is a blood-borne infection of the liver caused by the hepatitis C virus (HCV) which becomes chronic in about 85% of cases. According to a 2011 report from Decision Resources, about 180 million people worldwide are chronically infected with HCV. In addition, HCV infection is the leading cause of liver transplantation and is a risk factor for liver cancer. The global hepatitis market was estimated at $6 billion in 2011 and is forecasted to grow to $20 billion by the end of the decade.

About BioLineRx

BioLineRx is a publicly-traded biopharmaceutical development company dedicated to building a portfolio of products for unmet medical needs, as well as those with advantages over currently available therapies. The Company in-licenses novel compounds primarily from academic institutions and biotech companies based in Israel, develops them through pre-clinical and/or clinical stages, and then partners with pharmaceutical companies for advanced clinical development and/or commercialization.

BioLineRx's current portfolio consists of a variety of clinical and pre-clinical projects, including: BL-1040 for prevention of pathological cardiac remodeling following a myocardial infarction, which has been out-licensed to Ikaria Inc. and is in the midst of a pivotal CE-Mark registration trial; BL-5010 for non-surgical removal of skin lesions, which is expected to commence a pivotal CE-mark registration trial in late 2013; BL-8040 for treating acute myeloid leukemia (AML) and other hematological cancers, which is in the midst of a Phase 2 study; and BL-7010 for celiac disease, which is expected to commence a Phase 1/2 study in late 2013.

For more information on BioLineRx, please visit www.biolinerx.com or download the investor relations mobile device app, which allows users access to the Company's SEC documents, press releases, and events. BioLineRx's IR app is available on the iTunes App Store as well as the Google Play Store.

Various statements in this release concerning BioLineRx's future expectations, including specifically those related to the development and commercialization of BL-8020, constitute "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995. These statements include words such as "may," "expects," "anticipates," "believes," and "intends," and describe opinions about future events. These forward-looking statements involve known and unknown risks and uncertainties that may cause the actual results, performance or achievements of BioLineRx to be materially different from any future results, performance or achievements expressed or implied by such forward-looking statements. Some of these risks are: changes in relationships with collaborators; the impact of competitive products and technological changes; risks relating to the development of new products; and the ability to implement technological improvements. These and other factors are more fully discussed in the "Risk Factors" section of BioLineRx's most recent annual report on Form 20-F filed with the Securities and Exchange Commission on March 12, 2013. In addition, any forward-looking statements represent BioLineRx's views only as of the date of this release and should not be relied upon as representing its views as of any subsequent date. BioLineRx does not assume any obligation to update any forward-looking statements unless required by law.

Contact:

KCSA Strategic Communications

Garth Russell / Todd Fromer

+1 212-896-1250 / +1 212-896-1215

grussell@kcsa.com / tfromer@kcsa.com

or

Tsipi Haitovsky

Public Relations

+972-3-6240871

tsipih@netvision.net.il

SOURCE BioLineRx Ltd.

/Web site: http://www.biolinerx.com

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