February 25, 2014

FDA Hepatitis Update - Changes to the Victrelis (boceprevir) label

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On February 24, 2014, FDA approved an update to the Victrelis (boceprevir) label to include a new virologic futility rule. Specifically Section 2, Dosage and Administration, Table 1 was revised to state: If a patient has HCV-RNA results greater than or equal to 1000 IU/mL at treatment week 8, then discontinue three-medicine regimen.

This statement is also reflected in subsection 2.4 Discontinuation of Dosing Based on Treatment Futility: Discontinuation of therapy is recommended in all patients with 1) HCV-RNA levels of greater than or equal to 1000 IU per mL at TW8 (treatment week 8); or 2) HCV-RNA levels of greater than or equal to 100 IU per mL at TW12 (treatment week 12); or 3) confirmed detectable HCV-RNA levels at TW24 (treatment week 24).

You can view the complete revised Victrelis label and Medication Guide at Drugs@FDA.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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Taking stress out of hepatitis C

by Opiferum
February 25, 2014

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Stress is a part of life in today's fast lane. From sitting in traffic to spending too much time worrying about the future, there are plenty of forms of stress. As we all react to stress on an individual basis, what might be stressful to you is a very personal experience. Therefore, the way in which we recognize and manage stress is vital, especially if you live with hepatitis C. After all, the effects of stress on liver disease are numerous. They include decreased hepatic (liver) blood flow, severity of liver disease, elevated ALT levels, liver cell death and worsening of liver disease. Reading a long list of symptoms is stressful enough to read, so it is no wonder we can find ourselves suffering from stress without even realizing it. So ask yourself, do you know when was the last time you were stressed without realizing it? Identifying unrecognized stress is a task in itself, as it is so easy to push stressful thoughts into our subconscious where they will lay dormant. Sometimes, this is not only the most difficult form of stress to identify, but prevent. After all, it is impossible to guarantee when stress might strike. Self-awareness is a great way in which to realize for yourself how much unrecognized stress affects those of us living with the hepatitis C virus. Let's take a look at some ways in which to reduce stress.

S - strive for flexibility;
T - take time to decide where your boundaries are in a relationship;
R - relax and take a deep breath, as sometimes, the time it takes to breathe is all it takes to realize that a step back is the safest place to be;
E - eat hep C friendly food, because it will put less stress on your liver;
S - sleep when your body is telling you it needs rest;
S - seek clarification, because we can make wrongful interpretations of a situation based on second-guessing what the other person is thinking (or doing).

Such simple steps might sound silly, but there is a lot to be said about “keeping things simple”. This is because stress is more often a build up of reactions we store without realizing. Now that social-media is a large part of our modern world, we are faced with more pressure than ever before. Red-flag alerts, notifications and spam now command our attention on the internet. We might spend more time making comments on social networking sites than taking the time to talk to our loved ones, face-to-face. As well, we are at risk of not feeling safe on the world wide web. Have you had a holiday from the internet recently? If not, take the challenge and you might discover just how much less stressful it is to keep up with the virtual world!

Stress is like a toxic weed, it can grow in any condition without any food or nutrients. All it needs is a person not to be aware of it. Sometimes, the best way to deal with stress is to tune into one's self and truly feel what it feels like, so as to know what it really is. Not knowing how stress feels is almost more stressful than stress itself! For those of us that live with the hepatitis C virus, our reactions to situations might be more sensitive. This can make us more vulnerable to stress, which is why knowing how stress affects you is a unique and wonderful way in which to help reduce it. With just a few minutes per day, it is possible to learn to live with stress in a healthier way. It might just be as simple as becoming more flexible, or eating healthier food: it just depends on YOU.

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Hepatology

Volume 59, Issue 3, page 1209, March 2014

Correspondence

You have full text access to this OnlineOpen article

Anna L. McNaughton M.Sc.1, Emma C. Thomson Ph.D., MRCP1, Kate Templeton Ph.D.2, Rory N. Gunson FRCPath3, E. Carol McWilliam Leitch Ph.D.1

Article first published online: 13 JAN 2014

DOI: 10.1002/hep.26544

Copyright © 2013 Crown copyright. HEPATOLOGY Copyright © 2013 the American Association for the Study of Liver Diseases.

Potential conflict of interest: Nothing to report.

This article is published with the permission of the Controller of HMSO and the Queen's Printer for Scotland.

Supported by MRC grant 63785.

To the Editor:

The recently licensed direct-acting antivirals (DAAs) boceprevir and telaprevir used to treat hepatitis C virus (HCV) infection act in a genotype-specific manner. The potential outcome of DAA treatment regimes on mixed HCV infections, consisting of concurrent infection with more than one HCV genotype, has not been considered. Standard genotyping methods are only capable of identifying the dominant genotype present within a mixed infection sample, leaving minor genotypes undetected. We propose that DAA treatment of mixed infections may be associated with the occurrence of genotype switching, whereby a previously undetected minority variant drug-resistant genotype expands to replace the successfully treated majority variant genotype. Such genotype switching could in some cases result in nonresponse to DAA treatment and could also be incorrectly interpreted as reinfection if genotyping is not repeated following treatment failure. As a matter of urgency, there is a need to assess the prevalence and clinical impact of mixed HCV infections.

To determine the prevalence of mixed HCV infections in a cohort of patients infected with genotype (gt) 3a (n = 47) or 1a (n = 48), we designed gt1a- and gt3a-specific primers providing partial coverage of the envelope genes E1 and E2 of HCV. Nested reverse transcription (RT) polymerase chain reaction (PCR) reactions were performed using gt1a primers with gt3a-infected samples and vice versa. Amplicons were sequenced and used to construct maximum likelihood phylogenetic trees using the MEGA 5.0 software package to confirm genotype.

The sensitivity of the RT-PCR reactions, as determined by 90% detection limits calculated from serial endpoint dilution RT-PCR and probit analysis, was nine copies/reaction. Of the gt3a-infected patient samples, 10.6% (5/47) harbored minority variant gt1a strains, whereas none of the gt1a-infected patient samples contained gt3a as a minority strain.

These findings are in keeping with other studies that found mixed HCV infections at rates of 5%-25.3%.[1-3] Further work is required to assess the impact of minority variant strains on patients treated with DAA therapy. If relapse following dual therapy for gt3 infection is associated with emerging dominance of preexisting gt1 strains, screening of baseline patient samples using genotype-specific methods could result in improved treatment strategies; for example, the prescription of triple rather than dual antiviral therapy. More work is required to assess the impact of multiple genotype infection on clinical outcome, and this work is more pressing in the DAA era.

Anna L. McNaughton, M.Sc.1
Emma C. Thomson, Ph.D., MRCP1
Kate Templeton, Ph.D.2
Rory N. Gunson, FRCPath3
E. Carol McWilliam Leitch, Ph.D.1
1 MRC-University of Glasgow Centre for Virus Research, Glasgow, UK
2 Edinburgh Specialist Virology Centre, Edinburgh, UK
3 West of Scotland Specialist Virology Centre, Glasgow, UK

References

  1. Pham ST, Bull RA, Bennett JM, Rawlinson WD, Dore GJ, Lloyd AR, et al. Frequent multiple hepatitis C virus infections among injection drug users in a prison setting. Hepatology 2010;52:1564-1572. Abstract Full Article (HTML) PDF(325K) References Web of Science® Times Cited: 21
  2. Yun H, Kim D, Kim S, Kang S, Jeong S, Cheon Y, et al. High prevalence of HBV and HCV infection among intravenous drug users in Korea. J Med Virol 2008;80:1570-1575. Abstract PDF(114K) References Web of Science® Times Cited: 5
  3. Thomson, EC, Fleming VM, Main J, Klenerman P, Weber J, Eliahoo J, et al. Predicting spontaneous clearance of acute hepatitis C virus in a large cohort of HIV-1-infected men. Gut 2011;60:837-845. CrossRefWeb of Science® Times Cited: 24

Source

Journal of Viral Hepatitis

Early View (Online Version of Record published before inclusion in an issue)

V. Virlogeux1,2,3,4, P. Pradat1,2,3, F. Bailly1,2,3, G. Funingana1, F. Gonçalves1, M. Maynard1, K. Hartig-Lavie1, M. Amiri1, F. Zoulim1,2,3,5,*

Article first published online: 25 FEB 2014

DOI: 10.1111/jvh.12237

© 2014 John Wiley & Sons Ltd

Keywords: glomerular filtration rate;  hepatitis C virus;  pegylated interferon;  protease inhibitor;  renal function;  ribavirin; triple therapy; virological response

Abstract

Summary

Triple therapy using telaprevir or boceprevir [hepatitis C virus (HCV)-NS3/NS4A protease inhibitors (PI)] in association with PEG-IFN/ribavirin has recently become the new standard of care (SOC) for treatment of HCV genotype 1 patients. Our objective was to assess the efficacy and tolerance of triple therapy in routine clinical practice. A total of 186 consecutive HCV patients initiating triple therapy were enrolled in a single centre study. Clinical, biological and virological data were collected at baseline and during follow-up as well as tolerance and side effect details. Among 186 HCV patients initiating triple therapy, 69% received telaprevir and 31% boceprevir. Sixty-one per cent of patients had cirrhosis. The overall extended rapid virological response (eRVR) rate and sustained virological response (SVR) rate were 57.0% and 59.7%, respectively. IL28B CC phenotype was associated with increased probability of achieving eRVR and SVR, whereas previous non-response was associated with low eRVR and SVR rates. The SVR rate increased from 30.8% in previously non-responders to 59.1% in partial non-responders and 75% in relapsers. SVR rate in naive patients was 62.5%. Glomerular filtration rate assessed by MDRD after 12 weeks of therapy was significantly reduced for both PI (P < 0.001). The model for end-stage liver disease(MELD) score was significantly increased at W12 for telaprevir (P = 0.008) and at W24 for boceprevir (P = 0.027). PI-based triple therapy leads to high rates of virological response even in previously non-responder patients. Renal function after triple therapy is impaired as well as MELD score in all patients. Cautious clinical monitoring should focus not only on haematological and dermatological side effects but also on renal function.

Source

PUBLIC RELEASE DATE: 25-Feb-2014]

Contact: Dawn Peters
sciencenewsroom@wiley.com
781-388-8408
Wiley

Phase 2 trial results published in the March issue of Hepatology, a journal of the American Association for the Study of Liver Diseases, suggests the potential for Glycerol Phenylbutyrate (GPB) to reduce hepatic encephalopathy episodes in patients with cirrhosis, with a safety profile similar to placebo.

Patients with hepatic encephalopathy experience neuropsychiatric symptoms that may range from mild confusion to coma. There is conflicting evidence on the link between elevated blood ammonia and hepatic encephalopathy. Poorly-absorbable disaccharides and antibiotics are currently used to treat encephalopathy and are generally believed to act by reducing ammonia production in the intestine.

"GPB is approved to treat urea cycle defects that prevent the removal of ammonia from the body," explains Dr. Bruce F. Scharschmidt, Sr. VP & Chief Medical Officer with Hyperion Therapeutics in San Francisco, CA. "Our trial was the first to investigate the efficacy of a direct ammonia lowering agent in patients with cirrhosis and hepatic encephalopathy."

This phase 2 clinical trial enrolled 178 cirrhosis patients, including 59 who were already taking rifaximin. Participants who had two or more hepatic encephalopathy events within the six months prior to the trial were included. The trial aim was to determine the proportion of patients with hepatic encephalopathy taking 6mL GBP twice daily compared to placebo.

Results show that the percentage of patients who experienced hepatic encephalopathy events was significantly reduced among patients randomized to GPB versus placebo at 21% vs. 36%, respectively. Total hepatic encephalopathy events were lower in patients taking the medication (35) versus placebo (57). Hospitalizations due to hepatic encephalopathy tended to be less frequent among patients taking GPB at 13 compared to those in the placebo group at 25.

The trial results also indicate that ammonia levels in the blood of patients on GPB were lower than subjects not taking the medication. "Our findings provide evidence that elevated blood ammonia plays an important role in the development of hepatic encephalopathy," concludes Dr. Scharschmidt. "GPB reduced the risk of hepatic encephalopathy in patients with cirrhosis and further investigation of its therapeutic potential for patients with hepatic encephalopathy is warranted."

In a related editorial published in Hepatology, Dr. Meritxell Ventura-Cots with the Hospital Vall Hebron in Barcelona, Spain writes, "The study by Rockey et al. shows that GPB improves the outcome among cirrhotic patients with highly recurrent hepatic encephalopathy. The new drug avoids the risk of sodium overload, was well tolerated and had a good safety profile."

###

This study and editorial are published in Hepatology. Media wishing to receive a PDF of the articles may contact sciencenewsroom@wiley.com.

Full citations: "Randomized, Double-Blind, Controlled Study of Glycerol Phenylbutyrate in Hepatic Encephalopathy." Don C. Rockey, John M.Vierling, Parvez Mantry, Marwan Ghabril, Robert S. Brown Jr., Olga Alexeeva, Igor A. Zupanets, Vladimir Grinevich, Andrey Baranovsky, Larysa Dudar, Galyna Fadieienko, Nataliya Kharchenko, Iryna Klaryts'ka, Vyacheslav Morozov, Priya Grewal, Timothy McCashland, K. Gautham Reddy, K. Rajender Reddy, Vasyl Syplyviy, Nathan M. Bass, Klara Dickinson, Catherine Norris, Dion Coakley, Masoud Mokhtarani and Bruce F. Scharschmidt for the HALT-HE Study Group.Hepatology; (DOI: 10.1002/hep.26611) Print Issue Date: March, 2014.

URL: http://doi.wiley.com/10.1002/hep.26611

Editorial: "Drug-Induced Removal of Nitrogen Derivatives in Urine: A New Concept Whose Time Has Come." Juan Cordoba and Meritxell Ventura-Cots. Hepatology; (DOI: 10.1002/hep.26789) Print Issue Date: March, 2014.

URL: http://doi.wiley.com/10.1002/hep.26789

Author Contact: Media wishing to speak with Dr. Scharschmidt may contact Sylvia Wheeler with Hyperion Therapeutics at Sylvia.Wheeler@hyperiontx.com.

About the Journal

Hepatology is the premier publication in the field of liver disease, publishing original, peer-reviewed articles concerning all aspects of liver structure, function and disease. Each month, the distinguished Editorial Board monitors and selects only the best articles on subjects such as immunology, chronic hepatitis, viral hepatitis, cirrhosis, genetic and metabolic liver diseases and their complications, liver cancer, and drug metabolism. Hepatology is published on is published by Wiley on behalf of the American Association for the Study of Liver Diseases (AASLD). For more information, please visit http://wileyonlinelibrary.com/journal/hep.

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