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

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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Mixed genotype hepatitis C infections and implications for treatment

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. CrossRef,  Web of Science® Times Cited: 24

Source

Boceprevir and telaprevir-based triple therapy for chronic hepatitis C: virological efficacy and impact on kidney function and MELD score

Journal of Viral Hepatitis

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

V. Virlogeux^1,2,3,4, P. Pradat^1,2,3, F. Bailly^1,2,3, G. Funingana¹, F. Gonçalves¹, M. Maynard¹, K. Hartig-Lavie¹, M. Amiri¹, F. Zoulim^1,2,3,5,*

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

Glycerol phenylbutyrate reduces hepatic encephalopathy events And ammonia levels compared to placebo

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.

About Wiley

Wiley is a global provider of content-enabled solutions that improve outcomes in research, education, and professional practice. Our core businesses produce scientific, technical, medical, and scholarly journals, reference works, books, database services, and advertising; professional books, subscription products, certification and training services and online applications; and education content and services including integrated online teaching and learning resources for undergraduate and graduate students and lifelong learners.

Founded in 1807, John Wiley & Sons, Inc. (NYSE: JWa, JWb), has been a valued source of information and understanding for more than 200 years, helping people around the world meet their needs and fulfill their aspirations. Wiley and its acquired companies have published the works of more than 450 Nobel laureates in all categories: Literature, Economics, Physiology or Medicine, Physics, Chemistry, and Peace. Wiley's global headquarters are located in Hoboken, New Jersey, with operations in the U.S., Europe, Asia, Canada, and Australia. The Company's website can be accessed at http://www.wiley.com.

Source

Gilead – “Forget Me Not” HCV Disease Activation Commercial

 Gilead – “Forget Me Not” HCV Disease Activation Commercial from Gilead on Vimeo.

 

“Gilead is first to throw its hat into direct to consumer marketing for hepatitis C.”

 

This commercial (and campaign) is designed to get diagnosed patients to rethink treating their hepatitis C. And through empathy and understanding, we connect with hepatitis C patients and encourage them to take action by registering online at HepcHope.com and to talk to their gastroenterologist about scientific advances that may help them move on from hepatitis C.

 

Source

Celsion Announces FDA Clearance of the OPTIMA Study - A Pivotal Phase III Trial of ThermoDox in Primary Liver Cancer

PRESS RELEASE

Feb. 24, 2014, 8:00 a.m. EST

--Study Developed in Consultation with Clinical Advisors, Statistical Experts and FDA --Compelling Survival Data Supports Development --Trial Advances Global Regulatory Strategy in Key Markets

LAWRENCEVILLE, N.J., Feb. 24, 2014 /PRNewswire/ -- Celsion Corporation CLSN -0.27% announced today that the U.S. Food and Drug Administration (FDA) has reviewed and provided clearance for the Company's planned pivotal, double-blind, placebo-controlled Phase III trial of ThermoDox®, its proprietary heat-activated liposomal encapsulation of doxorubicin in combination with radio frequency ablation (RFA) in primary liver cancer, also known as hepatocellular carcinoma (HCC). The trial design is based on a comprehensive analysis of data from the Company's Phase III HEAT Study, which demonstrated that treatment with ThermoDox resulted in a 55% improvement in overall survival in a substantial number of HCC patients that received an optimized RFA treatment.  Celsion expects to launch the study in the first half of 2014.

The Phase III trial, known as the OPTIMA Study, was designed with extensive input from globally recognized HCC researchers and clinicians, and after formal consultation with FDA. The OPTIMA Study is expected to enroll 550 patients globally, with up to 100 sites in the United States, Europe, China and Asia Pacific and will evaluate ThermoDox in combination with RFA, which will be standardized to a minimum of 45 minutes across all investigators and sites for treating lesions 3 to 7 centimeters, versus standardized RFA alone. The primary endpoint for the trial is overall survival (OS).  The statistical plan calls for two interim efficacy analyses by an independent Data Monitoring Committee (iDMC).

"ThermoDox appears to hold great promise as a first-line treatment when used in combination with  optimized RFA, for primary liver cancer, one of the most deadly and prevalent forms of cancer worldwide," stated Nicholas Borys, MD, Celsion's Chief Medical Officer. "Consistency of the retrospective data emerging from the HEAT Study over the past year has been remarkable, and underscores the potential of ThermoDox to extend survival in primary liver cancer patients. Now informed by critical insights from our HEAT Study, I am confident that the OPTIMA Study is robust, well-designed and well-supported by HCC researchers worldwide.  We look forward to initiation and timely completion of this important study."

As reported in January 2014, post-hoc data from the Company's  HEAT Study demonstrate that the patient subgroup in the ThermoDox arm whose RFA procedure lasted longer than 45 minutes (285 patients or 63% of single lesion patients), experienced a 55% improvement in overall survival, with a Hazard Ratio of 0.64 (95% CI 0.41 - 1.00) and a P-value = 0.0495. Median overall survival for this subgroup has not yet been reached. Celsion will continue to follow patients in the HEAT Study on a quarterly basis.

"FDA allowance of the Phase III OPTIMA Study represents a significant step forward in our global development strategy for ThermoDox and establishes a clear regulatory pathway that advances our goal of delivering a new treatment option to patients with this devastating and underserved disease," stated Michael H. Tardugno, Celsion's President and CEO. "In parallel with our efforts in the United States, we continue to advance discussions with regulators in other important global markets, including a recent positive meeting with China FDA (CFDA) and near-term plans to meet with European regulatory authorities."

In support of the Company's global regulatory efforts, Celsion recently met with CFDA to discuss the Phase III trial, including minimum patient enrollment requirements supporting ThermoDox's registration in China. Based on those discussions, Celsion is submitting an application for accelerated approval of the study in China. Celsion will expand its clinical site footprint in Europe and plans to meet with the European Medicines Agency (EMA) in the first half of 2014.

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

About Celsion Corporation

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

Celsion wishes to inform readers that forward-looking statements in this release are made pursuant to the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995.  Readers are cautioned that such forward-looking statements involve risks and uncertainties including, without limitation, unforeseen changes in the course of research and development activities and in clinical trials; the uncertainties of and difficulties in analyzing interim clinical data, particularly in small subgroups; FDA and regulatory uncertainties and risks; the significant expense, time, and risk of failure of conducting clinical trials; HEAT Study data is subject to further verification and review by the HEAT Study Data Management Committee; the need for Celsion to evaluate its future development plans; possible acquisitions or licenses of other technologies, assets or businesses or the possible failure to make such acquisitions or licenses; possible actions by customers, suppliers, competitors, regulatory authorities; and other risks detailed from time to time in the Celsion's periodic reports and prospectuses filed with the Securities and Exchange Commission.  Celsion assumes no obligation to update or supplement forward-looking statements that become untrue because of subsequent events, new information or otherwise.

Celsion Investor Contact Jeffrey W. ChurchSr. Vice President and CFO609-482-2455jchurch@celsion.com

SOURCE Celsion Corporation

Source

Scientists Transform Skin Cells into Functioning Liver Cells

Joint Gladstone-UCSF Study Highlights Novel Reprogramming Method, Offers New Hope for Treating Liver Failure

By Jeff Norris and Anne Holden on February 23, 2014

The power of regenerative medicine now allows scientists to transform skin cells into cells that closely resemble heart cells, pancreas cells and even neurons. However, a method to generate cells that are fully mature—a crucial prerequisite for life-saving therapies—has proven far more difficult. But now, scientists at the Gladstone Institutes and UC San Francisco have made an important breakthrough: they have discovered a way to transform skin cells into mature, fully functioning liver cells that flourish on their own, even after being transplanted into laboratory animals modified to mimic liver failure.

Holger Willenbring, MD, PhD

In previous studies on liver-cell reprogramming, scientists had difficulty getting stem cell-derived liver cells to survive once being transplanted into existing liver tissue. But the Gladstone-UCSF team figured out a way to solve this problem. Writing in the latest issue of the journal Nature, researchers in the laboratories of Gladstone Senior Investigator Sheng Ding, PhD, and UCSF Associate Professor Holger Willenbring, MD, PhD, reveal a new cellular reprogramming method that transforms human skin cells into liver cells that are virtually indistinguishable from the cells that make up native liver tissue.

These results offer new hope for the millions of people suffering from, or at risk of developing, liver failure—an increasingly common condition that results in progressive and irreversible loss of liver function. At present, the only option is a costly liver transplant. So, scientists have long looked to stem cell technology as a potential alternative. But thus far they have come up largely empty-handed.

Sheng Ding, PhD

“Earlier studies tried to reprogram skin cells back into a pluripotent, stem cell-like state in order to then grow liver cells,” explained Ding, one of the paper’s senior authors, who is also a professor of pharmaceutical chemistry at UCSF, with which Gladstone is affiliated. “However, generating these so-called induced pluripotent stem cells, or iPS cells, and then transforming them into liver cells wasn’t always resulting in complete transformation. So we thought that, rather than taking these skin cells all the way back to a pluripotent, stem cell-like state, perhaps we could take them to an intermediate phase.”

This research, which was performed jointly at the Roddenberry Center for Stem Cell Research at Gladstone and the Broad Center of Regeneration Medicine and Stem Cell Research at UCSF, involved using a ‘cocktail’ of reprogramming genes and chemical compounds to transform human skin cells into cells that resembled the endoderm. Endoderm cells are cells that eventually mature into many of the body’s major organs—including the liver.

“Instead of taking the skin cells back to the beginning, we took them only part way, creating endoderm-like cells,” added Gladstone and CIRM Postdoctoral Scholar Saiyong Zhu, PhD, one of the paper’s lead authors. “This step allowed us to generate a large reservoir of cells that could more readily be coaxed into becoming liver cells.”

Next, the researchers discovered a set of genes and compounds that can transform these cells into functioning liver cells. And after just a few weeks, the team began to notice a transformation.

“The cells began to take on the shape of liver cells, and even started to perform regular liver-cell functions,” said UCSF Postdoctoral Scholar Milad Rezvani, MD, the paper’s other lead author. “They weren’t fully mature cells yet—but they were on their way.”

Now that the team was encouraged by these initial results in a dish, they wanted to see what would happen in an actual liver. So, they transplanted these early-stage liver cells into the livers of mice. Over a period of nine months, the team monitored cell function and growth by measuring levels of liver-specific proteins and genes.

Two months post-transplantation, the team noticed a boost in human liver protein levels in the mice, an indication that the transplanted cells were becoming mature, functional liver cells. Nine months later, cell growth had shown no signs of slowing down. These results indicate that the researchers have found the factors required to successfully regenerate liver tissue.

“Many questions remain, but the fact that these cells can fully mature and grow for months post-transplantation is extremely promising,” added Willenbring, associate director of the UCSF Liver Center and the paper’s other senior author. “In the future, our technique could serve as an alternative for liver-failure patients who don’t require full-organ replacement, or who don’t have access to a transplant due to limited donor organ availability.”

Other scientists who participated in this research include UCSF researchers Jack Harbell, MD, also a lead author on the paper, as well as Aras Mattis, MD, PhD, Alan Wolfe and Leslie Benet, PhD. Funding was provided by the following: the California Institute for Regenerative Medicine, the National Institutes of Health, the German Academic Exchange Service, and the Society of University Surgeons.

About the Gladstone Institutes

Gladstone is an independent and nonprofit biomedical-research organization dedicated to accelerating the pace of scientific discovery and innovation to prevent, treat and cure cardiovascular, viral and neurological diseases. Gladstone is affiliated with UCSF.

About UCSF

UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy, a graduate division with nationally renowned programs in basic biomedical, translational and population sciences, as well as a preeminent biomedical research enterprise and two top-ranked hospitals, UCSF Medical Center and UCSF Benioff Children’s Hospital.

Source

Hepatitis C to Share Spotlight at HIV Conference

Medscape Medical News > Conference News

Marcia Frellick

February 24, 2014

BOSTON — Although HIV will dominate the agenda at the 2014 Conference on Retroviruses and Opportunistic Infections (CROI), related viruses and infections will also be in the limelight.

Several presentations at the conference, being held from March 3 to 6, will focus on advances in the treatment of hepatitis C virus and the barriers to delivery, and the latest developments in tuberculosis (TB) and human papillomavirus.

Lynn Taylor, MD, from the division of infectious diseases at Miriam Hospital, Brown Medical School, in Providence, Rhode Island, told Medscape Medical News that developments in drugs and policy on the hepatitis C front make this year's discussion particularly important.

"We have seen extraordinary, unprecedented improvement in therapies to cure hep C," she said. "We have the potential to eradicate hep C locally, nationally, globally. The focus of our panel is that there's nothing in place yet, on any significant scale, to enhance delivery."

Dr. Taylor described a "crisis" in the United States because baby boomers who never knew they were infected are now discovering it in advanced form. "Seventy-five percent of Americans who have hep C don't even know they have it," she said.

“Ten years ago, you were considered a charlatan if you said hep C was curable.”

Last year, because of the prevalence of hepatitis C in baby boomers, the Centers for Disease Control and Prevention revised its guidelines to recommend a 1-time screening for everyone born from 1945 to 1965, in addition to risk-based screening. In December 2013, the European Association for the Study of the Liver revised its clinical practice guidelines on the management of hepatitis C; they will be presented in April before the International Liver Congress.

Dr. Taylor said she is "thrilled" to see the increased attention on hepatitis C at the conference.

"Ten years ago, you were considered a charlatan if you said hep C was curable," she said.

The conference, the most significant HIV research meeting in the world, will attract more than 4000 leading international HIV/AIDS researchers. The goal is to provide a forum for researchers to translate their findings into direct progress in HIV.

Conference to Draw More Than 4000 Researchers

Last year's conference was abuzz with the news that a 2-year-old Mississippi girl, born with HIV and treated early with antiretroviral drugs, had been functionally cured and no longer had detectable levels of the virus, despite not taking medication for 10 months.

This year, speakers will provide updates on the progress toward a cure for HIV, and look at what is standing in the way of getting there.

Adeeba Kamarulzaman, MBBS, from the University of Malaya in Kuala Lumpur, Malaysia, said she will explain some positive changes for drug users in the HIV fight in countries such as Malaysia.

She will also speak about the impact of the "epidemic of incarceration" and its effects on HIV, as well as coinfection with TB and hepatitis C, she told Medscape Medical News. She will highlight the increase in methamphetamine use and its relation to HIV risk behaviors, particularly in men who have sex with men.

TB is also getting attention at the conference. There will be presentations on the resistance, persistence, monitoring, and control of the disease; the use of novel imaging technology to monitor treatment response; and population-level control of HIV-related TB.

The prevention and treatment of HIV infection in infants will be addressed, as will the short- and long-term consequences of antiretroviral exposure during pregnancy and breast-feeding.

In addition, the outbreak of invasive meningococcal disease that affected men who have sex with men in New York City from 2010 to 2013 will be discussed.

Source

The Rise of Sofosbuvir

Infectious Disease Special Edition
ISSUE: FEBRUARY 2014 | VOLUME: 1

by Kate O'Rourke

Many clinicians are ecstatic about the recent approval of sofosbuvir (Sovaldi, Gilead Sciences) for patients with hepatitis C virus (HCV) infection. At The Liver Meeting 2013, several presentations provided new insight into just how sofosbuvir will perform in clinical practice.

“I think sofosbuvir is the cat’s meow,” said Sammy Saab, MD, MPH, professor of medicine and surgery and head of outcomes research in hepatology at the David Geffen School of Medicine, University of California, Los Angeles.

“It’s a drug that has no resistance or incremental adverse effects. It is very well tolerated, very safe, very efficacious and there are no significant drug interactions with it. I think it is going to revolutionize the way we treat hepatitis in this country and around the world.”

Traditional Risk Factors Fade Away

According to studies presented at The Liver Meeting, many factors traditionally thought to portend poor outcomes in HCV patients may not have an effect with sofosbuvir. One study was a retrospective analysis of 982 patients with HCV infection (genotypes 1-6) in four Phase III trials: FISSION, POSITRON, FUSION and NEUTRINO. Patients were treated with sofosbuvir plus ribavirin, with or without pegylated interferon (IFN). Sustained virologic response (SVR) rates were analyzed according to gender, age (<65 vs. ≥65 years), interleukin-28 B (IL28B) genotype, body mass index (<30 vs. ≥30 kg/m²), race (black vs. non-black), viral load (HCV RNA <10⁷ vs. ≥10⁷ copies/mL), opiate replacement status and cirrhosis. Of these factors, only male gender and the presence of cirrhosis were consistently predictive of worse outcomes; the difference between cirrhotics and noncirrhotics existed but was not large. In the NEUTRINO trial, for example, 80% of cirrhotics versus 92% of noncirrhotics achieved SVR at week 12. Also, IL28B genotype status was only predictive of SVR in the NEUTRINO trial.

HIV Coinfection

Sofosbuvir in combination with ribavirin also works well and causes less toxicity than IFN-based regimens in HCV patients who are coinfected with HIV. In the PHOTON-1 trial, 182 treatment-naive patients with HCV genotype 1, 2 or 3 and stable HIV disease, some of whom had cirrhosis, were evaluated. SVR rates at week 12 were 81% in HCV genotype 2 patients and 67% in HCV genotype 3 patients. Among the 19 patients not acheiving SVR at week 12, relapse was confirmed in 12 patients and data were missing for six patients. HCV genotype 1 patients received 24 weeks of treatment and had an SVR rate of 76%. Sofosbuvir was coadministered effectively with multiple HIV antiretroviral regimens, including inhibitors of HIV-1 protease, reverse transcriptase and integrase; it had no adverse effect on HIV status or antiretroviral therapy.

“The IFN-free regimen of sofosbuvir plus ribavirin resulted in high SVR 12 rates in HCV treatment-naive, HIV-infected patients with HCV genotype 1, 2 or 3 coinfection,” said Mark Sulkowski, MD, medical director of the Viral Hepatitis Center in the Divisions of Infectious Diseases and Gastroenterology & Hepatology, and professor of medicine at the Johns Hopkins School of Medicine, in Baltimore, who presented the study. “SVR 12 rates were similar to those observed in patients with HCV mono-infection.”

Null Responders

Data from the COSMOS trial suggested that HCV genotype 1 null responders may be a lot easier to treat with the combination of sofosbuvir plus simeprevir (Olysio, Janssen) than with first-generation direct-acting antiviral agents. In this Phase II trial, investigators evaluated 167 patients in two cohorts. In cohort 1, patients with METAVIR scores of F0 to F2 who were prior null responders to IFN with ribavirin received 12 or 24 weeks of treatment with sofosbuvir plus simeprevir, with or without ribavirin. In an intent-to-treat (ITT) analysis of the data, these patients achieved SVR rates at week 12 of 79% to 96%. Cohort 2 included treatment-naive patients and prior null responders with METAVIR scores of F3 to F4; they received 12 weeks of treatment with sofosbuvir plus simeprevir, with or without ribavirin. These patients achieved SVR rates at week 4 of 96% to 100%, based on an ITT analysis. The treatments were characterized as generally well tolerated.

“The findings in this interim analysis suggest that the addition of ribavirin to simeprevir plus sofosbuvir may not be needed to achieve high rates of SVR in this patient population,” said Ira Jacobson, MD, chief of the Division of Gastroenterology and Hepatology at Weill Cornell Medical College, New York City, who presented the data. “Anemia and bilirubin increases were predominantly limited to the ribavirin-containing treatment arms.”

Cirrhosis

Results from the LONESTAR-2 trial echoed results of other trials showing the high efficacy of sofosbuvir in prior null responders and patients with cirrhosis. This trial tested 12 weeks of treatment with sofosbuvir plus pegylated IFN and ribavirin in treatment-experienced patients with HCV genotype 2 or 3 infection. HIV and HBV coinfected patients were excluded from the trial, but 50% of the study population had compensated cirrhosis. In patients with HCV genotype 2 (n=23), 93% of cirrhotics and 100% of noncirrhotics achieved SVR at week 12. In HCV genotype 3 patients, the presence of cirrhosis did not affect outcomes, and 83% of patients achieved SVR at week 12.

“Sofosbuvir plus pegylated IFN/ribavirin for 12 weeks demonstrated high efficacy in treatment-experienced genotype 2/3 patients who have historically low response rates and limited treatment options,” said Eric Lawitz, MD, vice president of scientific and research development at The Texas Liver Institute and clinical professor of medicine at the San Antonio University of Texas Health Science Center, who presented the study. “SVR rates were similar in patients with and without cirrhosis.”

Different Treatment Duration for Patients With HCV Genotypes 2 and 3

Although many of the traditional factors that predict treatment response in HCV patients do not seem to apply to sofosbuvir, there does seem to be a difference in response among HCV genotypes. In general, clinicians are accustomed to treating patients with HCV genotype 2 or 3 similarly, but these two groups respond differently to sofosbuvir.

In Phase III trials, response rates have been higher in patients with HCV genotype 2 after 12 weeks of treatment with sofosbuvir plus ribavirin. The VALENCE trial originally set out to test 12 weeks of treatment with sofosbuvir plus ribavirin in patients with HCV genotype 2/3, but investigators amended the trial after recognizing that the two types of patients might respond to treatment differently; the 250 patients with HCV genotype 3 ultimately received 24 weeks of treatment. Among genotype 3 patients without cirrhosis, response rates were 94% in treatment-naive patients and 87% in treatment-experienced patients; genotype 3 patients with cirrhosis had response rates of 60%.

More evidence that longer therapy is better for HCV genotype 3 patients came from data presented at a meeting of the FDA Sofosbuvir Review team on Oct. 25.

“The FDA did an elegant analysis of the effect of treatment duration with sofosbuvir–ribavirin in genotype 3–infected patients,” Dr. Sulkowski said. “[They] presented very convincing data that a 24-week duration of sofosbuvir–ribavirin should be the standard for all genotype 3–infected patients.”

The FDA analysis combined data from the FISSION, POSITRON, FUSION and VALENCE trials. In both treatment-naive and treatment-experienced patients with HCV genotype 3, SVR rates dramatically rose and relapse rates fell when treatment was increased from 12 weeks to 24 weeks (Table).

As a result, when the FDA approved sofosbuvir in December, the agency approved a 12-week treatment regimen in patients with HCV genotype 2 and a 24-week regimen in patients with genotype 3, both in combination with ribavirin. The FDA also approved a 12-week regimen of sofosbuvir in combination with ribavirin and IFN for patients with HCV genotypes 1 and 4.

---

Dr. Saab has served as a consultant and on the speakers’ bureaus for Boehringer Ingelheim, Genentech, Gilead Sciences, Janssen, Merck, and Vertex Pharmaceuticals. Dr. Sulkowski has received consulting fees from Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Janssen, Merck and Vertex. Dr. Jacobson has received grants or research support and has served as a member of a speaker’s bureau or as a consultant/advisor for AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Idenix Pharmaceuticals, Janssen, Merck, Novartis, Roche/Genentech and Vertex. Dr. Lawitz has served on advisory committees or review panels for AbbVie, Achillion, BioCryst Pharmaceuticals, Biotica, Enanta, Idenix, Janssen, Merck, Novartis, Santaris, Theravance and Vertex; he has received grant and research support form AbbVie, Achillion, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Idenix, Intercept, Janssen, Merck, Novartis, Presidio, Roche, Santaris Pharma and Vertex.

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Bristol-Myers Squibb Receives U.S. FDA Breakthrough Therapy Designation for All-Oral Daclatasvir Dual Investigational Regimen for Chronic Hepatitis C

• FDA grants Designation request for investigational daclatasvir (DCV) and asunaprevir (ASV) combination therapy for treatment of genotype 1b chronic hepatitis C (HCV) infection
• Marks second Breakthrough Therapy Designation for a daclatasvir-based regimen; 3DAA regimen granted Designation in 2013

Monday, February 24, 2014 8:30 am EST

"The FDA’s decision to grant Breakthrough Therapy Designation for our DCV Dual Regimen (daclatasvir and asunaprevir combination therapy) marks the second time that the FDA has granted the Designation to a daclatasvir-based regimen, further underscoring its potential to help address the high unmet needs of the HCV patient population"

PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE:BMY) today announced that the U.S. Food and Drug Administration (FDA) has granted its investigational DCV Dual Regimen (daclatasvir and asunaprevir) Breakthrough Therapy Designation for use as a combination therapy in the treatment of genotype 1b chronic hepatitis C infection (HCV). The designation is based on data from the company’s ongoing Phase III clinical trial program evaluating the all-oral combination regimen of DCV, an investigational NS5A replication complex inhibitor, and ASV, an investigational NS3 protease inhibitor, without ribavirin.

According to the FDA, Breakthrough Therapy Designation is intended to expedite the development and review of drugs for serious or life-threatening conditions. The criteria for Breakthrough Therapy Designation require preliminary clinical evidence that demonstrates the drug may have substantial improvement on at least one clinically significant endpoint over available therapy.

“The FDA’s decision to grant Breakthrough Therapy Designation for our DCV Dual Regimen (daclatasvir and asunaprevir combination therapy) marks the second time that the FDA has granted the Designation to a daclatasvir-based regimen, further underscoring its potential to help address the high unmet needs of the HCV patient population,” said Brian Daniels, MD, senior vice president, Global Development and Medical Affairs, Research and Development, Bristol-Myers Squibb. “This is an important milestone for Bristol-Myers Squibb as we continue our strategic focus on the development of innovative medicines to address areas of high unmet medical need, where potential expedited review can make a critical difference for patients.”

Approximately 170 million people worldwide are infected with hepatitis C, with an estimated 2.7–3.9 million chronically infected in the U.S. Many of these people have been living with HCV for decades, putting them at heightened risk for developing serious, potentially life-threatening liver disease.

New data from Bristol-Myers Squibb’s ongoing Phase III clinical program studying the DCV Dual Regimen is anticipated to be presented at an upcoming scientific forum. Data from a separate daclatasvir and asunaprevir Phase III trial in Japanese patients with HCV genotype 1b who were either interferon-ineligible/intolerant or non-responders (null and partial) to interferon-based therapies served as the basis for a regulatory filing in Japan in October 2013.

Bristol-Myers Squibb also recently announced that the European Medicines Agency (EMA) validated the company’s marketing authorization application (MAA) for the use of daclatasvir for the treatment of adults with HCV with compensated liver disease, including genotypes 1, 2, 3, and 4. The application seeks the approval of daclatasvir for use in combination with other agents for the treatment of chronic hepatitis C and will be reviewed under an accelerated regulatory review.

About Hepatitis C

Hepatitis C is a virus that infects the liver and is transmitted through direct contact with infected blood and blood products. Up to 90 percent of those infected with hepatitis C will not spontaneously clear the virus and will become chronically infected. According to the World Health Organization, 20 percent of people with chronic hepatitis C will develop cirrhosis and, of those, up to 25 percent may progress to liver cancer.

About Bristol-Myers Squibb’s HCV Portfolio

Bristol-Myers Squibb’s research efforts are focused on advancing late-stage compounds to deliver the most value to patients with hepatitis C. At the core of our pipeline is daclatasvir, an investigational NS5A replication complex inhibitor that has been studied in more than 5,500 patients as a foundational agent for multiple direct-acting antiviral (DAA) based combination therapies.

In 2013, Bristol-Myers Squibb’s investigational all-oral 3DAA Regimen (daclatasvir/ asunaprevir/BMS-791325) received FDA Breakthrough Therapy Designation, which helped to expedite the start of the ongoing Phase III UNITY Program. Study populations include non-cirrhotic treatment naïve and experienced patients, as well as cirrhotic treatment naïve and experienced patients. The daclatasvir 3DAA regimen is being studied as a fixed-dose-combination treatment with twice daily dosing.

In addition, enrollment has begun for the Phase III ALLY Program, in which daclatasvir in combination with sofosbuvir, is being studied in high unmet need patients, such as pre- and post-transplant patients, HIV/HCV co-infected patients and patients infected with HCV genotype 3.

Other compounds in the pipeline include:

• Asunaprevir (ASV) is an investigational NS3 protease inhibitor for hepatitis C which has been studied as a component of DCV-based treatment regimens
• BMS-791325 is a non-nucleoside inhibitor of the NS5B polymerase, currently in Phase III development for hepatitis C as a component of DCV-based treatment regimens
• Peginterferon lambda is an investigational type III interferon that has the potential to offer an alternative to peginterferon alfa in patients for whom an interferon-based regimen is required or preferred

About Bristol-Myers Squibb

Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information, please visit http://www.bms.com or follow us on Twitter at http://twitter.com/bmsnews.

Bristol-Myers Squibb Forward Looking Statement

This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995 regarding the research, development and commercialization of pharmaceutical products. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. No forward-looking statement can be guaranteed. Among other risks, there can be no guarantee that DCV or any other compounds mentioned in this release will receive regulatory approval or, if approved, that they will become commercially successful products. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Bristol-Myers Squibb's business, particularly those identified in the cautionary factors discussion in Bristol-Myers Squibb's Annual Report on Form 10-K for the year ended December 31, 2013, in our Quarterly Reports on Form 10-Q and our Current Reports on Form 8-K. Bristol-Myers Squibb undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise.

Contact:

Bristol-Myers Squibb Company
Media:
Carrie Fernandez
Office: 609-252-4831
Cell: 215-859-2605
carrie.fernandez@bms.com
or
Investors:
Ranya Dajani, 609-252-5330
ranya.dajani@bms.com
or
Ryan Asay, 609-252-5020
ryan.asay@bms.com

Source

Impact of interferon free regimens on clinical and cost outcomes for chronic hepatitis C genotype 1 patients

J Hepatol. 2014 Mar;60(3):530-7. doi: 10.1016/j.jhep.2013.11.009. Epub 2013 Nov 19.

Younossi ZM¹, Singer ME², Mir HM³, Henry L⁴, Hunt S⁴.

Abstract

BACKGROUND & AIMS: Hepatitis C (HCV) is a common cause of chronic liver disease worldwide. Current standard treatment for genotype-1 patients uses a triple combination of pegylated-interferon alpha (IFN), ribavirin (RBV) and a direct-acting antiviral agent (DAA) with 75-80% sustained virologic response (SVR) rates. The aim is to determine cost-effectiveness of staging-guided vs. treat all HCV genotype-1 patients with interferon-based vs. interferon-free regimens.

METHODS: A decision analytic Markov model simulating patients until death compared four strategies for treating HCV genotype-1: Triple therapy (IFN, RBV, DAA) with staging-guidance or treat all, and oral IFN-free regimen with staging-guidance or treat all. Strategies with staging initiated treatment at fibrosis stages F2-F4, with staging repeated every 5years until age 70. The reference case was a treatment-naïve 50-year-old. Analysis was repeated for 50% increase in cost of oral therapy. Effectiveness was measured in quality-adjusted life years (QALYs).

RESULTS: Treatment of all patients with oral IFN-free regimen was the most cost-effective strategy, with an ICER of $15,709/QALY at baseline cost of oral therapy. The ICER remained below $50,000/QALY in sensitivity analyses for baseline and +50% cost of oral therapy scenarios. The treat all strategy was also the most effective strategy; associated with the lowest risk of developing advanced liver disease.

CONCLUSIONS: Treating all HCV patients with oral IFN-free regimen reduced the number of patients developing advanced liver disease and increased life expectancy. Additionally, IFN-free regimen without staging may be the most cost-effective approach for treating HCV genotype-1 patients. The efficacy and safety of these regimens must be confirmed using randomized clinical trials.

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

KEYWORDS: BOC, CHC, CMS, Centers for Medicare and Medicaid Services, Cost-effectiveness analysis, DAA, F0, F1, F2 or F4, GT, HCV, HIV, ICER, IFN, IFN, BV, DAA, Interferon-free oral treatment, Markov model, NADAC, National Average Drug Acquisition Cost, QALYs, RBV, SVR, TVR, Triple therapy, WAC, boceprevir, chronic hepatitis C, direct, acting antiviral agent, genotype, hepatitis C, immunodeficiency virus, incremental cost, effectiveness analysis, mild fibrosis, moderate or advanced fibrosis, pegylated, interferon alpha, quality, adjusted life years (a standard metric that incorporates both length and quality of life), ribavirin, sustained virologic response, telaprevir, wholesale acquisition cost

PMID: 24269472 [PubMed - in process]

Source

First Hepatitis C World Community Advisory Board Meeting

Provided by ACTUP-BASEL

Sunday 23 February 2014
All the versions of this article: [English]

February 22 – 25 2014 / Bangkok, Thailand

Organized by Treatment Action Group (TAG) with support from Asia Pacific Network of People Living with HIV/AIDS (APN+) and funded by TAG, the Open Society Institute, the World Health Organization, Médecins du Monde, Global Network of People living with HIV and AIDS Fonds. This first meeting will gather 40 international activists and should be the occasion to strategize together in order to increase HCV treatment access by addressing the following key issues: intellectual property, people who inject drugs (PWID), men who have sex with men (MSM), HCV DAA patent update and strategies for access, experiences of Asia and EECA CAB pharma negotiations, etc. In a second phase, activists will hold meetings with different originator and generic companies in order to clarify and make transparent the plans and policies of these companies.

AGENDA

Saturday, Feb. 22 (Day 1)

8:45 – 9:45 Welcome (K.Kaplan, TAG and S. Phurailatpam, APN+)
Participant introductions
Review meeting objectives, format, and expectations
Discuss meeting report

9:45 - 11:15 Basic DAA Literacy Training (T. Swan, TAG)

11:15 - 11:30 Coffee Break

11:30 - 12:30 Introduction to biosimilars (E.Torreele, A. Momen,OSF)

12:30 - 1:30 Lunch

1:30 - 3:00 Strategizing for HCV treatment access: addressing key intellectual property issues
Strategies for access to HCV treatments (P. Londeix, Act Up-­Basel)
Addressing key IP issues (P.Londeix, Act Up‐Basel, K. Bhardwaj, India)

3:00 - 3:15 Coffee Break

3:15 - 5:00 Patent opposition discussion

5:00 - 5:30 Wrap up

Sunday, Feb. 23rd (Day 2)

9:00 - 0:30 Key populations: people who inject drugs (PWID), men who have sex with men (MSM)
HCV situation, issues and access barriers for PWID (J.Byrne, INPUD)
HCV situation, issues and access barriers for MSM (N.Metheny, MSM-GF)

10:30 - 11:30 HCV DAA patent update and strategies for access (T. Amin, I-MAK)

11:30 - 11:45 Coffee Break

11:45 - 1:00 Pharmaceutical company approaches to HCV treatment access (P. Cawthorne, MSF; S. Collins, HIV i-base)
Pricing policies
Registration practices,
Voluntary licensing (Pros and Cons)

1:00 - 2:00 Lunch

2:00 - 3:00 Experiences of Asia and EECA CAB pharma negotiations (S. Phurailatpam, S. Golovin, ITPC-Ru)

3:00 - 4:30 Drug company meeting logistics (T. Swan, S. Collins)
Specific company introductions/background
Principles, format of Pharma and generic/biosimilar producer meetings
Statements, messages, demands (including meeting press release review)

4:30 - 4:45 Coffee Break

4:45 - 6:00 Drug company meeting logistics (continued)

6:00 - 6:30 Q&A, wrap‐up (Facilitator: K. Kaplan)

Monday, February 24th (Day 3) – Originator Companies

9:00-­‐11:00 Meeting with BMS

11:00 - 11:15 Coffee Break

11:15 - 1:15 Meeting with Abbvie

1:15 - 2:15 Lunch

2:00 - 4:00 Meeting with Janssen

4:15 - 4:30 Coffee Break

4:30 - 6:30 Meeting with Merck

Tuesday, February 25th (Day 4) – Originator Companies

9:00 - 11:00 Meeting with Roche

11:00 - 11:15 Coffee Break

11:15 - 12:00 Advocacy discussion

12:00 - 1:00 Lunch

1:00 - 4:00 Meeting with Gilead

4:00 - 5:00 Meeting with generic company

CLOSING

Source

Sleep Disorders in Cirrhotics; How can we detect?

Liver Int. 2014 Feb 10. doi: 10.1111/liv.12485. [Epub ahead of print]

Gencdal G¹, Gunsar F, Meral CE, Salman E, Gürsel B, Oruç N, Karasu Z, Ersöz G, Akarca US.

Abstract

INTRODUCTION: Sleep disorders (SDs) are common in cirrhotics and are often associated with hepatic encephalopathy. SDs negatively affect patients' daily activities and work efficiency. For this reason, early diognosis is important. The methods used for diagnosis of SDs are not practical and need longer periods of application and evaluation. In this study we aimed to investigate sleep disorders and related clinical parameters in liver cirrhosis and also want to investigate the using of Sleep Timing and Sleep Quality Screening questionnaire (STSQS), a simple form with a short application time, for diagnosis of SDs and its correlation with Pittsburg Sleep Quality Index (PSQI) form.

METHODS: Cirrhotic patients and age-matched healthy volunteers were enrolled. Patients were excluded from the study if they had neuropsychiatric disease or used excessive alcohol or drugs known to affect sleep. Both groups completed validated Turkish form of PSQI and STSQS. SD was defined as PSQI score (0-21) of >5 or STSQS≥5.

RESULTS: 131 cirrhotic patients and 18 healthy volunteers were enrolled. SDs in cirrhotics and control group were detected 56.5% and 27.8% by PSQI, 49.6% and 16.7% by STSQS respectively, SDs is the most frequent in the Child C patients, and the least frequent in the Child A patients (p>0,05). No correlation was found between the MELD score and SDs. SDs were more common in cirrhotic patients with hypoalbuminemia and low hemoglobin levels. In addition, the patients with decompensated cirrhosis had more frequently SDs than the patients with compensated cirrhosis. In the patient group, sleep latency and total sleep time, sleep parameters were correlated with SDs. STSQS had statistical significant correlation with PSQI for diagnosis of SDs.

CONCLUSION: SDs are common in cirrhotics and STSQS could be an appropriate and practical method for diagnosis of SDS in these patients. We can use it in cirrhotic patients at outpatient clinics. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

KEYWORDS: PSQI , STSQS , Liver Cirrhosis, Sleep, Sleep Disorders

PMID: 24512086 [PubMed - as supplied by publisher]

Source

No Risk of Worse Outcomes in Liver Transplantation With Hepatitis C-Positive Organs

Source: DGNews 

Presented at CEOT

By Nancy A. Melville

CHANDLER, Arizona -- February 18, 2014 -- The use of organs positive for hepatitis C virus (HCV) carries no increased risk of poorer outcomes among recipients who are also positive for HCV, according to research presented here at the American Society of Transplantation’s 2nd Annual Cutting Edge of Transplantation (CEOT) Meeting.

“Using the United Network for Organ Sharing (UNOS) and Scientific Registry of Transplant Recipients databases, we were able to demonstrate that since the introduction of the new organ allocation system in 2002 [Model for End-Stage Liver Disease or MELD system], HCV-positive recipients and the HCV serostatus of the donor do not have any impact on overall patient or graft survival,” said Martin Montenovo, MD, University of Washington, Seattle, Washington, on February 14.

For the study, Dr. Montenovo and colleagues evaluated 59,899 liver-transplant recipients aged ≥18 years in the UNOS database from 2002 to 2013.

Among the patients, 1,695 (2.8%) were HCV-positive recipients who had received HCV-positive allografts.

An analysis of differences in patient characteristics between recipients of HCV-positive and HCV-negative organs, as well as graft survival, showed that HCV-positive patients who received HCV-negative grafts were more likely to be hospitalised, in the intensive care unit, and on a ventilator and to have higher MELD scores and higher bilirubin.

Whereas patient and graft survival rates at 1, 5, and 10 years among HCV-positive recipients were inferior to HCV-negative recipients, there were no survival differences between HCV-positive patients who received HCV-positive or HCV-negative grafts.

“As far as we know, this is the first report looking at the effect of HCV donor status on HCV-positive recipients since the introduction of the MELD system,” Dr. Montenovo said. “All previous studies have shown some disparities in the results regarding the impact of the HCV donor status on patient and graft survival.”

The findings offer important evidence that the use of HCV-positive organs does not necessarily compromise outcomes, added Dr. Montenovo .

“The utilisation rate of this pool of donors has not changed over the years since the introduction of the MELD score allocation system,” he said.

“With the increasing number of HCV-positive recipients waiting for an organ in an era of significant organ shortage, more interest should be placed on HCV-positive donors who are often disregarded due to concerns of long-term outcomes,” Dr. Montenovo concluded. “Further large studies are needed to assess the impact, if any, of HCV-RNA donor status on outcomes.”

[Presentation title: The Clinical Impact of Hepatitis C-Positive Donors in Liver Transplantation: Patient Protection or Lost Opportunities? Abstract P-27]

Source

Cure of Hepatitis C Virus Infection Without Interferon Alfa: Scientific Basis and Current Clinical Evidence

Topics in Antiviral Medicine Volume 21 Issue 5 December 2013/January 2014

Perspective

Cure of hepatitis C virus (HCV) infection is achievable without interferon alfa through the use of new direct-acting antiviral (DAA) drugs. In this era of interferon alfa–sparing therapy, however, interferon alfa sensitivity still matters, even as it turns out, if interferon alfa is not used. Inclusion of ribavirin in the treatment regimen remains a factor in treatment response, as does duration of treatment. HCV genotype and subtype remain relevant considerations in choosing a treatment regimen, and viral resistance may emerge when treatment fails. The potency and barrier to resistance of new DAAs and the use of appropriately designed interferon alfa–sparing combinations can overcome obstacles to cure posed by HCV resistance, interferon alfa resistance, and differences in response based on HCV genotype and subtype. Studies demonstrating the use of new DAAs to overcome these obstacles are discussed. This article summarizes a presentation by David L. Thomas, MD, MPH, at the IAS–USA continuing education program held in New York, New York, in June 2013.

Keywords: HCV, hepatitis C, treatment, interferon, sparing, interferon alfa–sparing, direct-acting antivirals, DAAs, genotype, protease inhibitor, NS5A, NS5B, resistance, sofosbuvir, simeprevir

The first hepatitis C virus (HCV)-infected patients were cured in 1984 and 1985, before it was known that a virus was causing their disease. In studies at the National Institutes of Health (NIH), Hoofnagle and colleagues used interferon alfa to treat individuals with non-A or non-B hepatitis and observed a normalization of liver enzymes in these individuals.1 After the virus was identified, it became clear that eradication of HCV had also been achieved. Since then, interferon alfa has been the mainstay in the treatment and cure of HCV infection. Regimens that include interferon alfa have been associated with marked improvement in important therapeutic outcomes, including reductions in mortality, liver cancer, and other serious liver-related events. However, interferon alfa–based treatments are not always successful and have been associated with considerable toxicity and morbidity. Now, a new era of interferon alfa–sparing HCV treatment has begun, and soon it will be possible to achieve cure for most patients with as little as one pill once a day.

The Context

There are viral replication foci in approximately 10% to 20% of hepatocytes distributed throughout an HCVinfected liver. Approximately 1 to 50 viruses can be detected at any one time in a single hepatocyte, but there are places in the liver with no detectable HCV RNA. Thus, to be effective, HCV treatment must reach all sites in the liver that harbor infected hepatocytes. Further, in an HCV-infected liver, there are approximately 1 trillion viruses produced every day. If an environment becomes inhibitory for one variant, another will quickly take its place. To be successful, HCV treatment must also overcome the genetic and phenotypic heterogeneity of HCV. The ongoing host immune response to the virus sometimes clears infection. When it does not, those patients with chronic infection seem to have 1 of 2 different states. One state is characterized by inflammation and the upregulation of interferon-stimulated genes (ISGs). The HCV infections of persons with this high-ISG state are less responsive to exogenous interferon alfa, and these individuals often have a haplotype around the genes for the lambda interferons. In particular, the commercially available IL28B test to determine specific genotype indicates that individuals with a high-ISG state HCV infection have what is called the unfavorable IL28B T allele genotype. Persons with the other state have low expression of ISGs, and their HCV infections remain responsive to exogenous alpha-interferon. They are much more likely to have different genotypes near IL28B, and in particular, the favorable IL28B C allele genotype. Interestingly, persons in these 2 states of differing interferon sensitivity and the associated IL28B genotypes continue to have different susceptibilities to interferonsparing treatments, reflecting their intrinsic tendency to eradicate infection.

The context of infection can also be important when liver tissue is markedly distorted by cirrhosis. Patients with cirrhosis are harder to treat effectively, even with new interferon alfa–sparing regimens, possibly because the distorted tissue inhibits drug penetration or because of factors such as changes in portal pressure.

The Tools

Almost all of the major steps in the HCV life cycle are potential targets for inhibiting viral replication, including entry, endosomal release and internal ribosome entry site (IRES)-dependent translation, protease cleavages, membranous web formation and lipoprotein assembly linked to nonstructural protein (NS) 5A (NS5A), and NS5B RNAdependent RNA polymerase (RdRp) activity. Investigational drugs have been developed to target nearly all of these steps but several drugs are further along in development.

Currently, the 3 main groups of HCV drugs are protease inhibitors (PIs; ie, telaprevir and boceprevir), NS5Aacting agents, and nucleos(t)ide RdRp inhibitors. HCV PIs are potent, can affect a variable range of HCV genotypes, and have a variable barrier to resistance, especially with HCV genotype 1a compared with genotype 1b. Nucleos(t)ide polymerase inhibitors are characterized by high potency, can affect a wide range of HCV genotypes, and have a high barrier to resistance. NS5A-targeting drugs also have high potency, but their barrier to resistance has been problematic.

In formulating approaches to combination therapy, the strategy is to exploit the beneficial properties of the different drug groups and also to include a drug with a high barrier to resistance. In some cases, the investigation of drug combinations is limited by the practicalities of drug development, with drug companies developing combinations of their own products. Thus, some of the most obvious drug combinations for HCV therapy are not being tested in phase III trials.

Interferon Alfa–Sparing Treatment

Although there are data to show that HCV can be cured with investigational treatments that do not include interferon alfa, sensitivity to interferon alfa may still be a factor in treatment response and resistance may emerge when a treatment is unsuccessful. HCV genotype and subtype, ribavirin use, and duration of treatment may also be factors in the efficacy of HCV therapy. However, a drug’s potency or its barrier to resistance can trump these other factors.

Figure 1. Design of a trial evaluating the use of the investigational drugs faldaprevir and deleobuvir, with or without ribavirin, in 362 treatment-naive patients with genotype IL28B (CC or non-CC) and hepatitis C virus (HCV) genotype 1 (subtype 1a or 1b) infection. Thirty-three patients enrolled in the trial had compensated cirrhosis. BID indicates twice daily; QD, once daily; TID, thrice daily. Adapted with permission from Zeuzem et al.2

A study assessing the use of the investigational HCV PI faldaprevir (once daily) combined with the investigational nonnucleoside (nn) NS5B inhibitor deleobuvir (formerly BI 207127; twice or thrice daily), with or without ribavirin, for various treatment durations in treatment-naive patients with HCV genotype 1 infection illustrates many of these points (Figure 1).2,3 Substantial rates of sustained virologic response (SVR) 12 weeks after cessation of treatment (SVR12), considered to constitute cure, were observed with all regimens, indicating that cure of HCV infection is indeed possible without the use of interferon alfa (Figure 2).2 SVR12 rates were higher in the groups that received ribavirin, indicating that ribavirin may still impact the efficacy of HCV treatment. In the same study, IL28B genotype and interferon alfa sensitivity were still factors in treatment response, as shown by the higher SVR12 rates seen in patients with the IL28B CC genotype, regardless of which regimen they received (Figure 3, top).2 Furthermore, HCV subtype remained a factor, as shown by the higher SVR12 rates in patients with HCV genotype 1b versus genotype 1a infection, again regardless of which regimen they received (Figure 3, bottom).2 Several PIs show marked differences in their ability to eradicate genotype 1a virus compared with genotype 1b virus. In this study, the SVR12 rate in patients with HCV genotype 1a infection whose regimens did not include ribavirin was only 11%.2 Faldaprevir may be indicated for use only in patients with HCV genotype 1b infection.

Figure 2. Sustained virologic response (SVR) rates, by treatment group, in a trial evaluating the use of the investigational drugs faldaprevir and deleobuvir, with or without ribavirin, in treatment-naive patients with hepatitis C virus (HCV) genotype 1 infection. BID indicates twice daily; QD, once daily; SVR12, SVR 12 weeks after cessation of treatment; TID, thrice daily. Adapted with permission from Zeuzem et al.2

Figure 3. Sustained virologic response (SVR) rates, by treatment group, in a trial evaluating the use of the investigational drugs faldaprevir and deleobuvir, with or without ribavirin, in treatment-naive patients with genotype IL28B (CC or non-CC) and hepatitis C virus (HCV) genotype 1 (subtype 1a or 1b) infection, stratified by patient genotype (top) and HCV subtype (bottom). BID indicates twice daily; QD, once daily; SVR12, SVR 12 weeks after cessation of treatment; TID, thrice daily. Adapted with permission from Zeuzem et al.2

In another study, 19 treatmentnaive patients with HCV genotype 1 infection received a 12-week regimen of the ritonavir-boosted investigational PI ABT-450, the investigational nnNS5B inhibitor ABT-333, and ribavirin.4 Of these 19 patients, 47% had IL28B T genotype and 89% had HCV genotype 1a infection. All 19 patients achieved virologic suppression; SVR12 was achieved in 18 patients (95%), with 1 patient withdrawing from the study due to elevated levels of alanine transaminase. However, when the same regimen was given to 17 of the study patients whose previous regimen of interferon alfa and ribavirin had failed (all patients had IL28B T genotype and 94% of patients had HCV genotype 1a infection), SVR12 was achieved in only 8 patients (47%), 6 experienced breakthrough viremia, and 3 relapsed. Of the latter 9 patients, viral resistance developed in all but 1.

In a separate study, the same regimen was fortified with the investigational NS5A inhibitor ABT-267, which is highly potent but does not have a high barrier to resistance.5,6 As shown in Figure 4, SVR rates in patients with prior nonresponse to interferon alfa were 89% to 98% when ABT-267 was added to their regimen, with very few patients experiencing breakthrough or relapse. This study demonstrates that the addition of another drug can dramatically improve response rates by overcoming resistance to interferon alfa in those with prior nonresponse.

(Click to view larger image)

Figure 4. Sustained virologic response (SVR) rates, by treatment group, in a trial evaluating the use of the ritonavir-boosted (/r) investigational protease inhibitor ABT-450, the investigational nonstructural protein (NS) 5A (NS5A) inhibitor ABT-267, the investigational nonnucleoside NS5B inhibitor ABT-333, and ribavirin in 438 hepatitis C virus (HCV)-infected, treatment-naive patients and in 133 HCV-infected patients with prior nonresponse to interferon alfa. SVR12 indicates SVR 12 weeks after cessation of treatment; SVR24, SVR 24 weeks after cessation of treatment. Adapted with permission from Kowdley et al.6

Similar principles of treatment may be observed when a nucleotide inhibitor (ie, sofosbuvir) with broad genotypic activity is used with or without ribavirin in individuals with HCV genotype 2 or 3 infection. Sofosbuvir has been approved by the US Food and Drug Administration (FDA) since the June presentation summarized here.

In an initial study of sofosbuvir given with or without ribavirin to treatment-naive patients with HCV genotype 2 or 3 infection, the SVR24 rate was 100% (10 of 10) in patients who received sofosbuvir and ribavirin and 60% (6 of 10) in patients who received sofosbuvir monotherapy.7,8 Likewise, in 25 treatmentnaive patients with HCV genotype 1 infection who received a combination of sofosbuvir and ribavirin, the SVR24 rate was 84%. However, SVR24 was achieved in only 1 of 10 HCV genotype 1–infected patients with prior nonresponse to interferon alfa. Therefore, the use of sofosbuvir and ribavirin can achieve high SVR rates in treatment- naive patients who are relatively sensitive to interferon alfa, whether they have HCV genotype 1, 2, or 3 infection. However, as represented in patients with prior nonresponse, resistance to interferon alfa still plays a role and, as discussed below, it can be overcome.

A study of sofosbuvir and ribavirin in 201 patients with prior nonresponse and HCV genotype 2 or 3 infection demonstrated that genotype and duration of treatment were factors in achieving SVR.7 Among patients with HCV genotype 2 infection, SVR was achieved in 94% of those who received 16 weeks of treatment and in 86% of those who received 12 weeks of treatment. Among patients with HCV genotype 3 infection, SVR rates were lower but still reflected a benefit with longer treatment duration: SVR was achieved in 62% of the 16-week treatment group and 30% of the 12-week treatment group. Longer duration of treatment was also beneficial to patients with cirrhosis: SVR was achieved in 66% of the 16-week treatment group and 31% of the 12-week treatment group.9

In another study, the addition of the investigational NS5A-acting agent ledipasvir to a 12-week regimen of sofosbuvir and ribavirin produced SVR in 100% (9 of 9) of HCV genotype 1–infected patients with prior nonresponse and in 100% (25 of 25) of treatment- naive, HCV genotype 1–infected patients.10 Sofosbuvir and ledipasvir, coformulated as a single, once-daily pill, taken with or without ribavirin for a 12- or 16-week treatment period is currently being assessed in phase III trials.

Early phase studies have evaluated investigational HCV drugs from 2 different pharmaceutical companies. Although combination forms of these drugs do not seem destined for FDA approval anytime soon, there is some preliminary evidence that the treatments are effective. FDA approval of some of these individual drugs may offer clinicians the possibility of devising interferon alfa–sparing regimens in the very near future and prior to FDA approval of combination regimens.

For instance, simeprevir was recently approved by the FDA for use in combination with ribavirin and interferon alfa in HCV genotype 1–infected patients with compensated liver disease, including cirrhosis. And an early phase study has shown that the investigational combination of the PI simeprevir and the nucleotide inhibitor sofosbuvir, with or without ribavirin, produced SVR in more than 90% of HCV genotype 1–infected patients with prior nonresponse.11 Similarly, the combination of the investigational NS5A-acting agent daclatasvir and the nucleotide inhibitor sofosbuvir, with or without the addition of ribavirin, produced an SVR rate of nearly 100% in a study of 41 patients whose prior treatment with telaprevir, boceprevir, and interferon alfa plus ribavirin had failed.12

Conclusion

Interferon alfa–sparing treatment for HCV infection is coming. Presently, many practitioners are faced with the decision of whether to treat their patients with currently available drugs or to wait until new drugs are available. As availability of the newer options approaches, many practitioners are choosing to wait or are enrolling their patients in clinical trials that evaluate new treatments.

With the recent approval by the FDA of sofosbuvir in combination with ribavirin for patients with HCV genotype 2 or 3 infection and in triple therapy with interferon alfa and ribavirin for treatment-naive patients with HCV genotype 1 or 4 infection, waiting to begin treatment may no longer be necessary for some patients. The recent FDA approval of simeprevir to be used with peginterferon alfa and ribavirin for patients with HCV genotype 1 infection also makes possible the use of sofosbuvir in combination with simeprevir, but this combination is investigational and not approved by the FDA at this time. The combination was effective for some patients in the COSMOS (Combination of Simeprevir and Sofosbuvir in HCV Genotype 1 Infected Patients) study.11 In 2014, approvals of additional medications, including interferon alfa–sparing combination regimens for HCV genotype 1, are likely.

More data are needed to determine the best ways to use new treatments for HIV/HCV-coinfected patients and other special populations. Substantial drugdrug interactions between sofosbuvir and most antiretroviral drugs have not been observed, and sofosbuvir and ribavirin regimens are already being studied in HIV/HCV-coinfected patients.

Interferon alfa may still be used to treat HCV infection for the foreseeable future in settings where new treatments may initially be too expensive. However, the widespread use of interferon alfa–sparing treatment options for all HCV-infected patients, whether in resource-rich or resource-poor locales, can be envisioned.

Presented by Dr Thomas in June 2013. First draft prepared from transcripts by Matthew Stenger. Reviewed and edited by Dr Thomas in December 2013.

Financial Affiliations: Dr Thomas has received grants awarded to his institution from Gilead Sciences, Inc, and Merck & Co, Inc.

Additional Suggested Reading

Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Eng J Med. 2013;368(20):1878-1887.

References

1. Hoofnagle JH, Mullen KD, Jones DB, et al. Treatment of chronic non-A, non-B hepatitis with recombinant human alpha interferon. A preliminary report. N Engl J Med. 1986;315(25):1575-1578.

2. Zeuzem S, Soriano V, Asselah T, et al. Interferon (IFN)-free combination treatment with the HCV NS3/4A protease inhibitor BI 201335 and the non-nucleoside NS5B inhibitor BI 207127 +/- ribavirin (R): final results of the SOUND-C2 and predictors of response [Abstract 232]. 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD). November 9-13, 2012; Boston, Massachusetts.

3. Zeuzem S, Soriano V, Asselah T, et al. Faldaprevir and deleobuvir for HCV genotype 1 infection. N Engl J Med. 2013;369(7):630-639.

4. Poordad F, Lawitz E, Kowdley KV, et al. Exploratory study of oral combination antiviral therapy for hepatitis C. N Engl J Med. 2013;368(1):45-53.

5. Kowdley K, Lawitz E, Poordad F, et al. A 12- week interferon-free treatment regimen with ABT-450/r, ABT-267, ABT-333 and ribavirin achieves SVR12 rates (observed data) of 99% in treatment-naive patients and 93% in prior null responders with HCV genotype 1 infection. 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD). November 9-13, 2012; Boston, Massachusetts.

6. Kowdley K, Lawitz E, Poordad F, et al. Safety and efficacy of interferon-free regimens of ABT-450/r, ABT-267, ABT-333 +/- ribavirin in patients with chronic HCV GT1 infection: results from the AVIATOR study. 48th Annual Meeting of the European Association for the Study of the Liver. April 24-28, 2013; Amsterdam, The Netherlands.

7. Gane EJ, Stedman CA, Hyland RH, et al. Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J Med. 2013;368(1):34-44.

8. Gane E, Stedman C, Anderson J, et al. 100% Rapid virologic response for PSI- 7977 + ribavirin in genotype 1 null responders (ELECTRON): early viral decline similar to that observed in genotype 1 and genotype 2/3 treatment-naive patients. 19th Conference on Retroviruses and Opportunistic Infections (CROI). March 5-8, 2012; Seattle, WA.

9. Jacobson IM, Gordon SC, Kowdley KV, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med. 2013;368(20):1867- 1877.

10. Gane E, Hyland R, Ding X, et al. ELECTRON: 100% suppression of viral load through 4 weeks post-treatment for sofosbuvir + ledipasvir (GS-5885) + ribavirin for 12 weeks in treatment-naive and -experienced hepatitis C virus GT1 patients [Abstract 41LB]. 20th Conference on Retroviruses and Opportunistic Infections (CROI). March 3-6, 2013; Atlanta, Georgia.

11. Lawitz E, Ghalib R, Rodriguez-Torres M, et al. Suppression of viral load through 4 weeks post-treatment results of a oncedaily regimen of simeprevir + sofosbuvir virus GT1 null responders [Abstract 155LB]. 20th Conference on Retroviruses and Opportunistic Infections (CROI). March 3-6, 2013; Atlanta, Georgia.

12. Sulkowski M, Gardiner DF, Rodriguez- Torres M, et al. Sustained virologic response with daclatasvir plus sofosbuvir ± ribavirin (RBV) in chronic HCV genotype (GT) 1–infected patients who previously failed telaprevir (TVR) or boceprevir (BOC). 20th Conference on Retroviruses and Opportunistic Infections (CROI). April 24-28, 2013; Amsterdam, The Netherlands.

Top Antivir Med. 2014;21(5):152-156
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