November 30, 2013

Opposition to Sofosbuvir Patent in India




Sofosbuvir is a pipeline hepatitis C (HCV) drug that has been recommended for treatment by the US FDA and EMA. HCV is a significant public health issue for low- and middle-income countries, that are home to 90% of the 185 million people who are infected with HCV. Although HCV is curable, high drug prices make treatment inaccessible, leaving people at risk for liver cancer or liver failure.

I-MAK filed an opposition against Gilead/Pharmasset's patent applications because we believe that the technologies comprising these patent applications are known and therefore undeserving of a patent grant. We also believe that it is now time that People Living with HCV obtain affordable access to the drugs they need.

Legal Documents for Opposition to Sofosbuvir (India)

I-MAK's Pre-Grant Opposition To The Prodrug Application (Without Exhibits)

I-MAK's Pre-Grant Opposition To The Prodrug Application (With Exhibits)

Background Information

MSF Press Release

Pricing Information And Speculation

Treatment Action Group: HIV, HCV And TB Pipeline Report

Media Coverage

'Indian Health Activists Move To Prevent Gilead’s Drug Patent' - Financial Times

'Hepatitis C Drug: US Group Opposes Gilead’s Patent Request In India' - Hindu Business Line

'Gilead Attempt To Secure Patent On Hepatitis C Drug Opposed In India' - Times Of India

'US Group Seeks To Block Gilead Drug Patent In India' - Yahoo News

Except for publications commissioned or published by third parties all content on this site is licensed under a Creative Commons Attribution 3.0 License


Helpful Hepatitis C Links


These are some really wonderful and informative HCV websites:

(All links open into new windows)

HCV Advocate
"Welcome to - Here you will find information on hepatitis C (HCV), hepatitis C treatment options, articles, newsletters; information on living with hepatitis C ......"
"The goal of is to produce high-quality, accurate, and timely online information about treatment, management, and prevention of HIV, hepatitis B and C, HIV/HBV and HIV/HCV coinfection, and related conditions ......"

HCV Vets
" Educational Website & Support Forums are provided by past and presents members of the United States Military with Hepatitis C (HCV) to assist fellow Retirees/Veterans / Active Military and Dependents with awareness to the Hep C virus exposure methods during military service ......"

“Latest treatment news and information for patient advocates and people working in hepatitis in Europe …..”

Hep C News
"Welcome to the hepatitis C news community. Join us for news, views and features about hep C, read the real-life experiences of our guest bloggers, and learn about living well with the condition ......"

HepMag - Your Guide to Hepatitis (A Smart + Strong web publication)
”At Smart + Strong, we know that when you are armed with expert, unbiased health care information; when you are empowered and inspired to advocate for your needs; and when you can connect to others dealing with a similar health condition, you are more likely to survive-and thrive …...”


National Hepatitis C Helpline: Help4Hep
"Help.4.Hep is a trusted source of information, support and referrals .....”

CDC - Know More Hepatitis
"Why Baby Boomers Should Get Tested ...
More than 75% of adults with Hepatitis C are baby boomers. Baby boomers are people born from 1945 through 1965. Most of them don’t know they are infected."

Redefining the Hep C Journey
"Helping healthcare providers (HCPs) and advocates improve the lives of people with Hep C through education, information, and understanding ....."

Committed to Cure in HCV (Boehringer Ingelheim Pharma)
"Boehringer Ingelheim is pleased to announce the launch of, a new website for HCPs interested in HCV. With this online resource, we are committed to providing easy access to the latest information on HCV research and clinical practice. Here, you can find overviews of the Hepatitis C virus and HCV treatment options ....."

HCV: Master of Illusion -  “C the Virus” (AbbVie Pharma)
“Welcome to the first self-optimizing website from AbbVie for healthcare professionals. Here, your choices influence the very nature of our website. Every time you interact with the content, the look of our home page changes, reflecting what matters most to you and your peers.”

”Frontline Medical Communications (FMC) Clinical and Medical News divisions form the industry’s largest medical communications company. FMC serves more than 1 million physicians and other health care professionals with diverse print and interactive multimedia products and platforms, and live events …..”


Lucinda Porter, RN - Author, Hepatitis C Advocate and Health Educator
Creating a World Free of Hepatitis C one step at a time

I Help C
"Welcome to Your Best Friend Guide to Hepatitis C ...."

Hepatitis C Awareness
"..... I think, as I have always believed, that peer to peer support is crucial in acquiring knowledge, understanding, as well as support from others who are going through, or have gone through living with and treating Hep C ......"


Updated November 30, 2013 9:49 pm EST

Personal Stories: Shared by Those Living With HCV

I am looking for people who would like to share their story of living and/or treating or caring for someone with HCV. I would like to put a human side to this insidious disease instead of all research. The way that I have the blog set up now it has more of the feeling of a website and I am able to add more sections. If you are interested in sharing your story here please email me at

(All links open into new windows)

January 08, 2014 My HCV Story by Debbie Cole

December 11, 2013 Mark (Thursdays Child) Eckler: What a gift!!

December 05, 2013 The Faces of Hepatitis C … A Poem by Selles Dole

December 05, 2013 I'm coming out ... A Poem by Nancy Burklin

December 05, 2013 Living with Hepatitis C and Its’ Effects – Anonymous

December 05, 2013 Jerome Alex: Where to start? At my birth … Part 2

December 02, 2013 Rita Robinson: Living with Hepatitis C

December 01, 2013 John Strother: My Life with Hepatitis C

December 01, 2013 Manaun Middleton: Road to Destruction

November 30, 2013 My Story of Strength and Hope with HCV – Anonymous

November 26, 2013 Bernie Miller: My Journey with Hepatitis C

November 22, 2013 Jerome Alex: Where to start? At my birth.

November 22, 2013 Jenne Griffin-Accettura: My HCV Journey

November 18, 2013 Terrie Lenhart-Jenson: My Personal HCV Story

November 17, 2013 HCV is for Hope, Courage, Victory. – Opi Ferum

March 25, 2013 Hepatitis C: From Bed to Book – Lucinda K. Porter, RN

March 13, 2013 My Story – Daryl Luster

Updated January 08, 2014 6:39 pm EST

New Hepatitis C Drug Approved: Janssen’s Hepatitis C Drug Simeprevir Now Available

Provided by Liver Specialists of Texas

The Blog of Dr. Joseph S. Galati
Discussions about the liver and everything else related to health and wellness.

by DR. JOE GALATI on 11/29/2013

This past week, the FDA gave approval to Janssen’s new drug to treat hepatitis C. Simeprevir, commercially know as OLYSIO, is the first new hepatitis C drug since the release of telapravir (Incevik) and boceprevir (Victrelis) in 2011. Simeprevir is a  NS3/4A protease inhibitor, used in combination with interferon and ribavirin.

The release of simeprevir marks the beginning of a new wave of direct acting antiviral agents against the hepatitis C virus. Additional drugs are set for FDA approval, including the Gilead drug sofosbuvir in early December 2013.

Most of the new hepatitis C drugs will have a number of features in common. These include:

  • Very high cure rate, in the 80-90% range – lower in null and non-responders
  • Less side effects
  • Shorter duration of treatment
  • Less pills to take each day
  • Cirrhosis reduces response rates
  • Less drug-drug interactions
  • Genotype 1 subtype differences exist

Looking at the dosing of simeprevir, I have attached the official product insert that describes how the drug will be doses. Several points to consider:

  • This is an interferon/ribavirin based therapy
  • Patients with genotype 1 need additional screening for the NS3 Q80K polymorphism
  • Those with this variant have a decreased response rate to the therapy, and should be considered for an alternative therapy
  • The initial dosing is 12 weeks of simeprevir with interferon and ribavirin, followed by an additional 12 or 36 weeks of interferon and ribavirin combination therapy.
  • There are drug-drug interaction which have to be monitored closely
  • FDA approval is for genotype 1 patients only

While the release of simeprevir is welcomed, it has not provided the proverbial “home-run” we have been looking for in our quest to cure hepatitis C. In well selected patients, achieving a better than 80% cure rate is available. The concerns I have relate to the Q80K polymorphism noted above. This will be an additional step required in screening our patients. Additionally, in patients with prior non-response or null responders, as well as those with cirrhosis, these patients will still require a full 48 week of interferon and ribavirin. One of the goals of the next generation of hepatitis C therapies is reduced interferon exposure, or complete elimination. Simeprevir does not fully meet this goal.

In the days to come, I will post additional information on sofosbuvir. For now, these are the highlights to consider (refer to this FDA document for additional details):

  • Sofosbuvir will likely receive FDA approval for Genotype 1,2,3, and 4 patients with hepatitis C
  • Interferon-free treatment in genotype 2 and 3 for 12 weeks
  • Sofosbuvir combined with interferon and ribavirin in genotype 1 and 4 for 12 to 16 weeks

This treatment strategy is far different than the simeprevir treatment noted above.

Looking further, we will eventually have all interferon-free protocols. It is anticipated that as additional new drugs are approved, they will be combined (example sofosbuvir and simeprevir), allowing us to treat a wide range of patients, safely, and with a cure rate many of us may have never envisioned 20 years ago.

For a consultation to see if you are a candidate for these new drugs, contact Lexa at our office at 713-794-0700 and visit our webpage for additional information.


My Story of Strength and Hope with HCV

November 30, 2013


I was born in 1984 and when I was 8 months old I was diagnosed with AML- Acute myelogenic leukemia. I underwent a heavy regiment of chemotherapy and received blood transfusions. Those things alone cured me of my leukemia and I was in remission from that when I was 2 years old.

When I was a freshman in high school, I found out I had hepatitis C. At that time little was known about it. I went and saw a hepatologist and they said I wouldn't need to undergo treatment at that time.

My freshman year high school biology teacher pulled me aside after class one day and asked why I was jaundice. I told her without thinking about any issues that I had hepatitis C. She pushed her wheeled chair backwards into the chalkboard and said I couldn't be at school. She literally wheeled herself over to her telephone and called the principle's office telling them I needed to immediately go over there and talk with the principle and the nurse about being pulled out of school. They in turn called my parents, my mom came to the school and explained that hepatitis C is only transferrable through blood, so it was of no concern. The teacher insisted my mom and I were mistaken and I needed to leave. We left that day, and my mom (who also worked for the school district) went to the superintendent at the school board for the district and explained that the teacher was being discriminatory and if anyone should be "expelled" from school, it was her. Sure enough, I stayed and she left.

Somehow or another, word got out to my friends, my boyfriend, and basically every kid in the entire school. It seemed to me at the time like the gossip and lies about me had spread like wildfire. No one would come near me, everyone was scared to be around me other than two senior girls I became friends with. So, I sunk into a weird funk and just spent time with them, always looking onwards to my usual group of friends. I ignored the comments when I was in swim team practice that they hoped the chlorine would kill any way of me giving them hepatitis. I ignored the kids who purposely sat as far away as they could in class from me. I ignored everyone except those two girls that be-freinded me through it all. Freshman year ended for me and those two graduated. The entire summer I spent alone, mostly in my room. I didn't want to talk to anyone, not my parents, no one about it. That is until I got a call from a long time friend growing up (who went to a different high school) that his dad had hepatitis C and end stage chirrosis and needed a liver transplant and he needed someone to talk to that understood. So, we started hanging out and in a way we found peace and hope in each other away from all the negativity of everyone else. Sophomore year came and I was dreading it every day that got closer. This time around I knew I'd have no one to talk to period, and it was depressing. My grades started slipping, I didn't care about school, I didn't pay attention to anyone or anything in class. I just remember sitting in every class, in the back row corner, in silence. When semester grades came out, my counselor told me I'd have to most likely take at least one extra semester of school because I was falling behind. She also had me start talking to a senior counselor. He had non-hodgkins lymphoma and was so kind and became a very good friend of mine. I found myself hanging out with him and trailing behind him like a puppy dog wherever he went, whenever possible at school. I stuck it out until February that school year,then got a call from a friend outside of school I'd also grown up with that she was going to be homeschooled through a charter school as of the very next day. I took that as my sign to get the heck out of public school, and so I did. I ended up graduating a year early with a 3.8 gpa, and got through 3 semesters of college while in school.

I met a guy in college and we ended up in a 3 year long relationship. Meanwhile, my parents split up and my mom moved away. My dad got together with another woman and basically all of this happened when I was 17. I started treatment for hepatitis C, per my new gastroenterologist. I went on what was available at that time- the double therapy - interferon and ribavarin. According to my genotype (1a) I was supposed to be on in for one year. My white blood cell counts plummeted to nearly zero and I was put on neupogen. While they did raise up, it was still in the danger zone, so I was cut off treatment at 6 months. I was basically in bed for that entire six months with no energy and extreme pain from the medication.

I went through a few year period of self medicating with street drugs of all varieties. My boyfriend and I split up, and I moved to a different place on my own. I already had a promising career under my belt which I managed to hold onto through all of it.

When I was 20 years old I met a couple and another guy who were thinking of leaving the town we lived in and travel all over. I was intrigued and interested in coming with them, but at the same time scared to leave my "normal" life behind. So, they headed out on their own without me. It wasn't long before one ended up in jail, the other went back home and the third I literally ran into when walking around a corner. I was shocked to say the least to see him. He told me of all the events, and I ended up taking him in. He slept on my floor in my room for a few months. We ended up getting into contact with the one that had been in jail and about to be released. We ended up leaving together and meeting up with him. Once again, the fellow that had been in jail was arrested again after a few days. I lost my car in the whole ordeal and found myself with my friend who has been with me on my bedroom floor, alone and on the streets...homeless. We found a quiet area and a mattress and slept in that little place for a few months. Meanwhile he professed his love to me on the city train. He was always such a quiet guy and blurted this out one day out of the blue. I was speechless and neither one of us said anything for a few days. I finally spoke up and told him I loved him, too...and so our relationship began.  In no time I got pregnant. I quit my drug habit immediately. We lived on the streets for the first 7 months of my pregnancy and took a trip halfway across the country through all of it. We ended up back at my mom and now stepdads house.  He got a job, and before we knew it, our daughter was born. Due to hepatitis it was recommended I have a cesarean- scheduled.  I had a cesarean, but she was born a month early. She spent 9 days in the NICU, but came home finally and continued on to grow up to be a healthy child as she is today.

Her dad continued his drug habit, lost his job, and I went back to work 2 weeks after I had her. We ended up leaving the area my parents lived in and moved back to where we started. That ended in a violent episode between him and I, so I went back to my moms place with our daughter. He followed us there, claimed he had changed, and was let back in. We were still living at my parents when there was another violent episode that nearly ended in me losing my life. Instead, it ended in him going to jail. He got out and told me I had to come with him or he would take care of me for good and take our daughter away from me. So, I complied and left with him. Again, we returned to our original home area.  We then travelled further north and landed in Portland, Oregon. There was more and more violence coming from him and I finally mustered up the courage to leave him. I got a restraining order against him, involved child protective services, who took legal custody of her until I could gain sole custody of her.  He apparently, took off to the east coast and I never saw him again. A year after the last time I saw him, he committed suicide with a cocktail of drugs in his system. The coroner said he also had hepatitis C, and considering what drugs he had in his system, most likely contracted it from IV drug use.

I spent about a year on my own until I was introduced to a man who I started dating. After about a year, we got married, and right around the time we got married I got pregnant with my now youngest child. We moved to a different area of the country together, which, after 6 months failed and ended in abuse on his part towards me and my oldest daughter. I gained full custody of our daughter, and have had custody of her since. We moved back to my home town and I tried to start over. One thing led to another and i found myself with two children living in my friend's parents house.

Not long after I was living there I met a homeless guy, who also had hepatitis c. We ended up getting in a relationship, moved to a different, then moved to where we are now. After many years of total lack of insurance, I am finally able to have insurance and start to take care of my medical needs. It's come out of the woodwork that I also have fibromyalgia, long term issues from chemotherapy, degenerative disk disease, cervical disk disorder, Raynaud's Syndrome, hyperthyroidism, hormonal issues, scoliosis, sciatica, vitamin deficiencies, and the list goes on. He couldn't handle trying to take care of me and my medical issues and the children, so he left. I am glad for that. As stressful as it may be at times to be a single parent, I am free, I am happy and I have my children and we share an unconditional love and unbreakable bond.

I'm taking it one day at a time, like I always have. I've found looking back never does any good. Looking forward can be stressful, too, sometimes. But looking straight ahead, or sometimes down at your feet to be sure ya still got them planted on the ground firmly is the only way to go. Adventures, crisis, death, sorrows...this is all a part of life...a part of my life I never would have experienced had the doctors not saved me in the beginning when I had leukemia. Good bad or indifferent I wouldn't change anything about my life. It hasn't been easy, and it may get harder from here but I'm not going to worry about what will come. I just worry about today, and am grateful I woke up this morning and made it through another day with air in my lungs. I always look at it as no one's life is truly any worse or better than the next person's- we all have learning experiences, challenges, love, hope, sorrow, and everything that life can throw at us- but they are all our experiences and we can embrace them and take them in the best way we can and learn so much about others and ourselves. No matter what happens in your life, you have to fight for yourself and protect who you love and that will give you undying peace and happiness. I am thankful for each and every day, no matter what may happen.


Persistence of Hepatitis C Virus during and after Otherwise Clinically Successful Treatment of Chronic Hepatitis C with Standard Pegylated Interferon α-2b and Ribavirin Therapy

PLoS One. 2013 Nov 21;8(11):e80078. doi: 10.1371/journal.pone.0080078.


Annie Y. Chen, Marija Zeremski, Ranjit Chauhan, Ira M. Jacobson, Andrew H. Talal, Tomasz I. Michalak


Resolution of chronic hepatitis C is considered when serum HCV RNA becomes repeatedly undetectable and liver enzymes normalize. However, long-term persistence of HCV following therapy with pegylated interferon-α/ribavirin (PegIFN/R) was reported when more sensitive assays and testing of serial plasma, lymphoid cells (PBMC) and/or liver biopsies was applied. Our aim was to reassess plasma and PBMCs collected during and after standard PegIFN/R therapy from individuals who became HCV RNA nonreactive by clinical testing. Of particular interest was to determine if HCV genome and its replication remain detectable during ongoing treatment with PegIFN/R when evaluated by more sensitive detection approaches. Plasma acquired before (n = 11), during (n = 25) and up to 12–88 weeks post-treatment (n = 20) from 9 patients and PBMC (n = 23) from 3 of them were reanalyzed for HCV RNA with sensitivity <2 IU/mL. Clone sequencing of the HCV 5′-untranslated region from plasma and PBMCs was done in 2 patients. HCV RNA was detected in 17/25 (68%) plasma and 8/10 (80%) PBMC samples collected from 8 of 9 patients during therapy, although only 5.4% plasma samples were positive by clinical assays. Among post-treatment HCV RNA-negative plasma samples, 9 of 20 (45.3%) were HCV reactive for up to 59 weeks post-treatment. Molecularly evident replication was found in 6/12 (50%) among PBMC reactive for virus RNA positive strand collected during or after treatment. Pre-treatment point mutations persisted in plasma and/or PBMC throughout therapy and follow-up. Therefore, HCV is not completely cleared during ongoing administration of PegIFN/R otherwise capable of ceasing progression of CHC and virus commonly persists at levels not detectable by the current clinical testing. The findings suggest the need for continued evaluation even after patients achieve undetectable HCV RNA post-treatment.

Citation: Chen AY, Zeremski M, Chauhan R, Jacobson IM, Talal AH, et al. (2013) Persistence of Hepatitis C Virus during and after Otherwise Clinically Successful Treatment of Chronic Hepatitis C with Standard Pegylated Interferon α-2b and Ribavirin Therapy. PLoS ONE 8(11): e80078. doi:10.1371/journal.pone.0080078

Editor: Stephen J. Polyak, University of Washington, United States of America

Received: July 29, 2013; Accepted: October 2, 2013; Published: November 21, 2013

Copyright: © 2013 Chen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This study was supported by an operating grant MOP-126056 from the Canadian Institutes of Health Research (CIHR) awarded to TIM. AYC is supported by the Canada Research Chair allowance provided by Memorial University. TIM holds the Senior Canada Research Chair in Viral Hepatitis/Immunology sponsored by the Canada Research Chair Program and funds from the CIHR and the Canada Foundation for Innovation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.


Hepatitis C virus (HCV) is a single-stranded RNA virus that is the cause of clinically diagnosable chronic infection in approximately 170 million people worldwide. Of those acutely afflicted, 15% spontaneously resolve hepatitis, while the remaining develop chronic hepatitis C (CHC) [1]. Up to15% of the patients with CHC progress to fibrosis and cirrhosis, and they are at a greater risk of developing hepatocellular carcinoma (HCC) [2]. HCV is infectious even in trace amounts, with approximately 10 virions or 20 copies of viral RNA capable of transmitting infection in chimpanzees [3], [4] and with 20 to 50 virions able to establish productive infection in human T cells in vitro [5]. The introduction of nucleic acid amplification assays detecting HCV genomes with high sensitivity, i.e., <10 virus genome equivalents (vge) or copies/ml or <2.5 vge/µg RNA (<2 IU/ml), revealed that HCV persists at low levels (usually below 100 vge/ml) for years after clinical resolution of hepatitis either spontaneously or due to treatment with interferon-α (IFN) alone or pegylated IFN/ribavirin (PegIFN/R) [6], [7]. The long-term consequences of this essentially asymptomatic infection, termed as occult HCV infection (OCI), remains uncertain; however, OCI coincides with histologically evident protracted low grade liver inflammation and fibrosis in some patients for at least 10 years after completion of antiviral treatment [8][11]. Also, clinically diagnosed sustained virological response (SVR) achieved due to IFN or PegIFN/R does not universally prevent progression to HCC, which develops in up to 3.9% of these individuals [12][17]. Contrary to prevailing opinion based on the currently available clinical testing for HCV RNA, clinical diagnosis of SVR does not reflect molecular eradication of HCV, as evidenced by assays of enhanced sensitivity supplemented with examining of serial samples of plasma, peripheral blood mononuclear cells (PBMC) and, when available, liver biopsies, and by procedures enriching HCV in test material by amplifying viral RNA recovered from larger amounts of serum, liver biopsy material and/or from mitogen-stimulated PBMC [6][9], [18][20]. Further, the detection of HCV RNA replicative (negative) strand is not uncommon in OCI, particularly when ex vivo stimulated PBMC and liver biopsy material are analysed [6], [8], [11], [20]. Since discovery of OCI in 2004, persistence of HCV after SVR was the subject of studies by different groups which delineated virological and some unique immunological properties of this infection [6][9], [21][23]. Among others, OCI displays a distinct profile of antiviral cytokine expression in PBMC when compared to either CHC or healthy individuals, shows an antagonistic relation between HCV and IFN-α expression in PBMC, and that HCV replication in this compartment can be completely eliminated by activation of endogenous IFN-α [22], [23]. Nonetheless, OCI is rarely investigated and knowledge on this subject remains incomplete. To broaden characterization of this infection entity, in particular to learn about the fate of HCV during and shortly after completion of otherwise clinically successful treatment with PegIFN/R, we re-examined, using highly sensitive HCV genome detection methods, serial plasma and, in some cases, PBMC samples collected prior to, during and after completion of PegIFN/R therapy from patients with CHC who finally achieved clinical SVR.

Materials and Methods

Ethics Statement

The study was approved by the Weill Cornell Medical College institutional review board and was performed in accordance with the Declaration of Helsinki. The samples were collected after signing written informed consent.

Patients and samples

Serial plasma samples (n = 56) from 9 patients (3 men and 6 women; ages 38 to 62), who clinically resolved CHC in response to treatment with PegIFN/R, and sequential PBMC samples (n = 23) from 3 of them were investigated (Table 1). The patients were infected with HCV genotype 1 or 2 (Table 1). The origin and the route of HCV infection were undetermined; however none of the patients was an active drug user during treatment or follow-up. None of them also was co-infected with hepatitis B virus (HBV) or human immunodeficiency virus or was receiving immunosuppressive or anti-cancerous therapy. All patients received PegIFN/R treatment for 24 or 48 weeks (wks) with the exception of 6/F, 7/F and 2/F who were treated for 25, 44 or 68 wks, respectively (median treatment time for all 9 patients was 43.3 wks) (Table 1). The therapy resulted in the decline of plasma HCV RNA to undetectable levels, as measured by clinical laboratory tests (see below), and in normalization of liver enzymes, i.e., alanine aminotransferase (ALT) and aspartate aminotransferase (AST), starting within 3 to 4 wks after initiation of PegIFN/R. In regard to plasma samples, 11 samples from a total of 19 collected prior to initiation of the therapy (pre-treatment samples) were available for re-examination. These 11 samples were obtained between week 21 and one before the start of treatment (median time of collection 8.1 wks). Among 55 plasma samples collected during the treatment period (on-treatment samples), 25 were available for re-evaluation (Table 1). Also, from 34 plasma samples collected during follow-up lasting for up to 88 wks after completion of PegIFN/R therapy (post-treatment samples), 20 were available for reanalysis. The time of the last sample collection from individual patients ranged between 12 and 88 wks post-treatment (median 33.1 wks). Plasma was stored in 1-mL aliquots at −80°C until re-tested. One 1-mL aliquot per sample was available for investigation.

Continue reading full article here - (Free) …..

Chutes and Ladders in Hepatitis C Nucleoside Drug Development

Antiviral Res. 2013 Nov 22. pii: S0166-3542(13)00339-2. doi: 10.1016/j.antiviral.2013.11.008. [Epub ahead of print]

Coats SJ, Garnier-Amblard EC, Amblard F, Ehteshami M, Amiralaei S, Zhang H, Zhou L, Boucle SR, Lu X, Bondada L, Shelton JR, Li H, Liu P, Li C, Cho JH, Chavre SN, Zhou S, Mathew J, Schinazi RF.

RFS Pharma, LLC, 1860 Montreal Road, Tucker, GA 30084, USA.


Chutes and Ladders is an exciting up-and-down-again game in which players race to be the first to the top of the board. Along the way, they will find ladders to help them advance, and chutes that will cause them to move backwards. The development of nucleoside analogs for clinical treatment of hepatitis C presents a similar scenario in which taking shortcuts may help quickly advance a program, but there is always a tremendous risk of being sent backwards as one competes for the finish line. In recent years the treatment options for chronic hepatitis C virus (HCV) infection have expand due to the development of a replicon based in vitro evaluation system, allowing for the identification of multiple drugable viral targets along with a concerted and substantial drug discovery effort. Three major drug targets have reached clinical study for chronic HCV infection: the NS3/4A serine protease, the large phosphoprotein NS5A, and the NS5B RNA-dependent RNA polymerase. Recently, two oral HCV protease inhibitors were approved by the FDA and were the first direct acting anti-HCV agents to result from the substantial research in this area. There are currently many new chemical entities from several different target classes that are being evaluated worldwide in clinical trials for their effectiveness at achieving a sustained virologic response (SVR) (Pham et al., 2004; Radkowski et al., 2005). Clearly the goal is to develop therapies leading to a cure that are safe, widely accessible and available, and effective against all HCV genotypes (GT), and all stages of the disease. Nucleoside analogs that target the HCV NS5B polymerase that have reached human clinical trials is the focus of this review as they have demonstrated significant advantages in the clinic with broader activity against the various HCV GT and a higher barrier to the development of resistant viruses when compared to all other classes of HCV inhibitors.

Copyright © 2013. Published by Elsevier B.V.

KEYWORDS: Antiviral, Clinical evaluation, HCV, Hepatitis C virus, Nucleoside analog, Nucleotide analog, Prodrug

PMID: 24275341 [PubMed - as supplied by publisher]


Hepatitis C prevention and treatment for substance users in the UnitedStates: acknowledging the elephant in the room

International Journal of Drug Policy 15 (2004) 81–91


Brian R. Edlin

Center for the Study of Hepatitis C, Weill Medical College of Cornell University, New York, NY, USA

Received 20 March 2002; received in revised form 3 October 2003; accepted 9 October 2003

Like many countries, the United States faces a major epi-demic of hepatitis C virus (HCV) infection. Nearly 3 millionAmericans are estimated to be infected with HCV (Alteret al., 1999),and some 35,000 new infections are believed tooccur annually (Williams, 1999).The virus causes chronicinfection in about 85% of those infected, and among thosechronically infected, cirrhosis may eventually develop infrom 5 to 20% (Freeman et al., 2001;Liang, Rehermann,Seeff, & Hoofnagle, 2000).HCV infection is thought to re-sult in 8000–10,000 deaths annually. It is already the mostcommon cause of chronic liver disease and the most com-mon reason for liver transplantation in the United States,and morbidity and mortality from HCV infection are risingand are expected to continue rising in the coming decades(Armstrong, Alter, McQuillan, & Margolis, 2000).

In the United States, as in many other developed coun-tries, injection drug users (IDUs) constitute the largest groupof persons infected with HCV, and most new infectionsoccur in IDUs. Injection drug use predominates as a modeof transmission in most countries where the endemicity of HCV is low. There are probably a million or more currentIDUs with HCV infection in the U.S.; of the estimated1.2–1.3 million current IDUs in the U.S. (Normand, Vlahov,& Moses, 1995), some 80–90% have been infected withHCV (Lorvick, Kral, Seal, Gee, & Edlin, 2001;Thomaset al., 1995),although recent studies have shown that preva-lence rates in young IDUs and recent initiates are now muchlower (Garfein et al., 1998;Hahn, Page-Shafer, Lum, Ochoa,& Moss, 2001;Thorpe, Ouellet, Levy, Williams,&Monterroso, 2000).The incidence of new infections amongIDUs is also quite high, however, generally ranging from10 to 20% per year in the U.S. (Garfein et al., 1998; Haganet al., 1999, 2001; Hahn et al., 2001; Thorpe et al., 2000).

The situation is similar in other developed countries (Crofts,Jolley, Kaldor, van Beek, & Wodak, 1997;Patrick et al.,2001;Van Ameijden, Van den Hoek, Mientjes, & Coutinho,1993;van Beek, Dwyer, Dore, Luo, & Kaldor, 1998).Moreover, initiation of heroin use and injection drug use isincreasing among young people (CDC, 2001a).Controllingthe HCV epidemic, therefore, will require developing, test-ing, and implementing prevention and treatment strategiesthat will be effective for persons who inject drugs. Fortu-nately, substantial research and clinical experience exists inthe prevention and management of chronic viral infectionsamong IDUs, particularly because of the HIV epidemic.Learning from this experience will be critical for efforts tocontrol HCV

The public health response to the HCV epidemic in theU.S. to date has, unfortunately, fallen short of what is neededto stop the epidemic. Until recently, official documents pro-duced by the U.S. Public Health Service about its responseto the HCV epidemic were silent on most of the interven-tions described in this article (CDC, 1998; CDC, 2001b;NIH, 1997a).In 2002, NIH issued an updated ConsensusStatement on the Management of Hepatitis C that took asubstantially more comprehensive approach to the problem(NIH, 2002).This statement challenges the medical, scien-tific, and public health communities to address numerousproblems that remain unsolved and continue to contribute tothe HCV epidemic.

Preventing morbidity and mortality from HCV can bedivided into primary, secondary, and tertiary prevention(Table 1).This paper summarises recommendations for ef-fective prevention in each of these categories, and discussessome of the barriers that have hampered their implementa-tion.

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Muscle Cramps in Liver Disease

Clinical Gastroenterology and Hepatology
Volume 11, Issue 11 , Pages 1385-1391, November 2013

Shivang S. Mehta, Michael B. Fallon

University of Texas Health Science Center at Houston, Houston, Texas

published online 01 April 2013.

Muscle cramps are common in patients with liver disease and adversely influence quality of life. The exact mechanisms by which they occur remain unclear, although a number of pathophysiological events unique to liver disease may contribute. Clinical studies have identified alterations in 3 areas: nerve function, energy metabolism, and plasma volume/electrolytes. Treatments have focused on these particular areas with varied results. This review will focus on the clinical features of muscle cramps in patients with liver disease and review potential mechanisms and current therapies.

Keyword: Chronic Liver Disease

Abbreviations used in this paper: ATP, adenosine triphosphate, MAP, mean arterial pressure, PRA, plasma renin activity, QOL, quality of life

Muscle cramps are defined as involuntary painful contractions at rest or during sleep of a muscle or muscle group that may last for seconds to minutes and are usually self-limiting.1, 2 Cramps are commonly found in a variety of diseases including liver disease (Table 1).3, 4 Although generally benign, the frequency and severity of cramps may be debilitating and have a significant negative effect on the quality of life (QOL) in affected patients. Despite the association of muscle cramps with liver disease, there is a paucity of information regarding pathogenesis and treatment in these patients.

Table 1. Diseases, Medications, and Physiological Changes Associated With Muscle Cramps

Prevalence and Clinical Significance 

The first report of an association between cirrhosis and muscle cramps was made by Konikoff and Theodor5 in 1986. Of 33 patients with cirrhosis who were studied, 88% were found to have experienced more than 2 cramps in calf muscles within the prior week. Since this report, several subsequent studies have demonstrated a 22%–88% prevalence of muscle cramps in patients with liver disease, depending on differing definitions, frequency, and inclusion criteria (Table 2).5, 6, 7, 8, 9, 10, 11The majority of studies have found a higher prevalence of cramps in cirrhotic patients relative to control groups. In addition, patients with cirrhosis in comparison with noncirrhotic patients with liver disease have been found to have a greater prevalence of cramps, 31% vs 5%, respectively.7 Abrams et al8 compared patients with cirrhosis with those with congestive heart failure and found a significantly higher prevalence of weekly or daily cramps with cirrhosis (22%) vs patients with congestive heart failure (5%). Interestingly, there was no difference in diuretic use or dosing between the 2 groups, supporting that factors other than diuretic-mediated effects explained the differences. Together, these studies suggest that unique physiological changes may occur in cirrhosis and predispose to the development of cramps.

Table 2. Prevalence of Muscle Cramps in Patients With Cirrhosis

The presence of cramps in cirrhosis also adversely influences QOL. Symptom experience in a cohort of 129 patients with cirrhosis found muscle cramps to be the second leading cause of distress and increased intensity of pain.3 Marchesini et al12 surveyed 544 patients with cirrhosis by using the Nottingham Health Profile and the Medical Outcome Study Short Form-36 questionnaires. Muscle cramps were identified as the most frequent variable associated with poor health-related QOL. In fact, muscle cramps were an independent impairment variable in both the physical and mental components of the questionnaire and were a significant factor in impairment in 13 of 14 domains.12, 13 A recent study investigated the QOL of cirrhotic patients experiencing cramps by using the Chronic Liver Disease Questionnaire, a more sensitive and specific survey for determining QOL in this particular group.11, 14, 15 Chatrath et al11 questioned 150 patients with cirrhosis and cramps and found significantly lower Chronic Liver Disease Questionnaire scores that were due to lower domain scores in abdominal symptoms, fatigue, systemic symptoms, activity, emotional functions, and worry relative to cirrhotic patients without cramps. These studies suggest that muscle cramps take a mental and physical toll on affected cirrhotic patients.


The pathophysiological mechanisms of muscle cramps in patients with cirrhosis are not clearly elucidated. However, a number of mechanisms have been considered and explored. Potential mechanisms may be divided into alterations in 3 overlapping areas: (1) nerve function, (2) energy metabolism, and (3) plasma volume and electrolytes (Figure 1).

Figure 1. Potential mechanisms and treatments of muscle cramps in cirrhosis. AAA, aromatic amino acid; BCAA, branched-chain amino acid.


Nerve Function 

The first studies examining the role of nerve dysfunction in patients with liver disease were conducted 30 years ago. At that time, it was postulated that nerve dysfunction was likely due to impaired membrane conduction as a result of oxidative stress.16 Histologic studies revealed that those with liver disease exhibited thinly myelinated nerve fibers and axonal loss, supporting the presence of structural damage.17 In addition, patients with cirrhosis were observed to have involuntary bursts of action potentials that appeared as fasciculations on electromyogram with origins in the peripheral nerve.18 These findings suggested a chronically depolarized and hyperexcitable motor neuron in patients with liver disease, thus inducing inappropriate high-frequency repetitive firing of the motor nerve action potentials, resulting in muscle cramps.17, 19, 20 This concept was expanded by Ng et al,21 who performed direct nerve studies on the median and peroneal motor nerves in patients with cirrhosis. The study found increased nerve excitability that was due to depolarization of the resting axonal membrane potential resulting from a significant reduction in threshold potential. These studies supported that nerve dysfunction, possibly related to oxidative injury and structural alterations, plays an important role in sustained muscle contractions and the development of muscle cramps. Therefore, a number of treatments have focused on decreasing the excitability of motor neurons and relieving oxidative injury within nerves.

Energy Metabolism 

The liver has a central role in amino acid and protein metabolism and is responsible for the deamination and modification of amino acids and the synthesis of amino acids into proteins.22 The regulation of amino acid and protein metabolism is altered in those with cirrhosis, which is reflected by decreased plasma and skeletal muscle concentrations of taurine (the most abundant amino acid in skeletal muscle). Altered taurine concentrations appear to result from both decreased production related to an imbalance in the ratio of branched-chain amino acids to aromatic amino acids and increased release from muscle.22, 23, 24 Taurine concentrations influence the function of a number of critical ion channels, including voltage-dependent chloride channels and calcium-activated sodium and potassium channels, which modulate striated fiber electrical activity and stabilize the sarcolemma.25, 26 The net result of taurine deficiency is a decrease in the threshold potential and hyperexcitability of skeletal muscle.27 Yamamoto et al28 directly measured the mean plasma taurine level in cirrhotic patients with and without muscle cramps in comparison with controls by using high-performance chromatography and found significant differences. The mean plasma taurine level in cirrhotic patients with cramps was 56.9 nmol/mL, whereas in those without cramps it was 79.3 nmol/mL, and healthy controls had a level of 90.1 nmol/mL. These findings support that taurine deficiency may alter skeletal muscle electrical properties, thereby predisposing these patients to cramps.

Another potential contributor to altered energy metabolism in cirrhosis is a reduction in adenosine triphosphate (ATP) production. Moller et al29 performed skeletal muscle biopsies in 10 cirrhotic patients and found a reduction in ATP, phosphocreatine, and total adenine nucleotide levels. A lack of ATP could diminish the cycling process of actin and myosin cross-bridging, causing prolonged muscle contraction particularly in the presence of abnormal electrical activity.

Plasma Volume, Electrolytes, and Zinc 

Electrolyte abnormalities including hyponatremia, hypokalemia, and hypomagnesemia as well as shifts in plasma volume that can influence intracellular concentrations of electrolytes or cause hypovolemia have been implicated as factors in producing cramps.30, 31, 32 Angeli et al9 sought to determine whether plasma volume, plasma renin activity (PRA), mean arterial pressure (MAP), serum albumin, and electrolyte concentrations affected the occurrence of muscle cramps in 224 patients with cirrhosis with and without ascites compared with 194 healthy controls. In multivariate analysis only higher PRA, presence of ascites, and lower MAP were predictors of cramps occurring in patients with cirrhosis because serum electrolyte concentrations of sodium, potassium, phosphorus, and magnesium had no effect on cramp occurrence. These studies would support that shifts in plasma volume may influence cramps, possibly by decreasing perfusion to nerves. In the same year, Abrams et al8 compared 92 patients with cirrhosis, 40 with chronic hepatitis without evidence of cirrhosis, and 40 patients with congestive heart failure to control for diuretic use. This study found similar results to that of Angeli et al in that no clinically significant difference in serum electrolyte concentrations was observed between cirrhotic patients with and without cramps. Also in multivariate analysis, diuretic use was not a significant contributor for the occurrence of cramps (P = .48). Subsequent studies confirmed these results and found no significant difference in the concentrations of zinc, sodium, potassium, magnesium, or calcium in cirrhotic patients with and without cramps.10, 11 Together, these results suggest that shifts in plasma volume may contribute to cramps, whereas serum electrolyte concentrations and diuretic use do not directly influence the frequency of cramps in patients with cirrhosis. However, intracellular concentrations of electrolytes could influence muscle excitability and have not been measured in cirrhotic patients with and without cramps.


Therapies for muscle cramps in cirrhosis are generally directed at the 3 potential pathophysiological mechanisms or are empiric (Table 3).

Table 3. Potential Mechanisms of Action of Agents Used to Treat Cramps in Cirrhotic Patients

Nerve Function

Vitamin E 

Vitamin E is a fat-soluble vitamin with α-tocopherol as the major biologically active form. It has potent antioxidant effects and also stabilizes the phospholipid bilayer of cell membranes.33 Vitamin E deficiency in animal models results in myocyte necrosis and in humans in myopathy.34, 35 Von Herbay et al36 demonstrated that lower serum vitamin E levels were found in alcoholic liver disease, hemochromatosis, and Wilson's disease compared with healthy controls. Two additional studies have reported on treatment with vitamin E for cramps in patients with cirrhosis. Konikoff et al6 recruited 29 patients with cirrhosis and found 23 with cramps. Those with cramps had significantly lower serum vitamin E levels than those without cramps (6.3 ± 3.2 vs 11.5 ± 4.8 μg/mL, P = .01). Thirteen subjects were treated with vitamin E (200 mg 3 times daily for 4 weeks) and had significant improvement on the basis of a scoring system assessing cramp severity, frequency, and duration. A subsequent pilot randomized, double-blind, placebo-controlled crossover study in 9 adult cirrhotic subjects found no statistical significance between vitamin E and placebo in the frequency (P = .98), duration (P = .93), or severity of muscle cramps (P = .57).37 However, treatment dosage and duration of treatment in the vitamin E arm were not reported. Both studies identified no significant side effects to treatment. Further studies are needed to assess whether vitamin E is effective in treating cramps and to define whether serum vitamin E levels might predict responsiveness.

Quinine sulfate 

Quinine, an alkaloid powder derived from the bark of the cinchona tree, was first reported as a treatment for muscle cramps in patients without cirrhosis in the 1940s.38, 39 Although the mechanism of action of quinine in cramps is not elucidated, it is believed to reduce the excitability of the motor nerve by prolonging the refractory period of muscle to repetitive stimuli.40, 41 A number of studies and a recent meta-analysis comparing quinine with vitamin E for the treatment of muscle cramps in noncirrhotic subjects found improvement with both agents but no significant difference in efficacy between them.2 A single study has investigated quinidine sulfate (optical isomer of quinine) for the treatment of muscle cramps in cirrhosis. Lee et al42 conducted a single-blind study in 31 cirrhotic patients with a history of cramps at least twice weekly for the preceding year. Sixteen patients received quinidine sulfate 200 mg twice daily for 4 weeks, and these patients had a significant reduction in the number of episodes of cramps during treatment (14.4 ± 1.7 to 4.4 ± 1.1, P < .0001) relative to the placebo group (11.8 ± 1.0 to 11.5 ± 1.5, P > .05). Mild diarrhea (31%) was the only side effect reported in the treatment group. Quinine is no longer available over-the-counter in the United States because of rare significant adverse effects including thrombocytopenia, cardiac arrhythmias, hemolysis, and cinchonism.43 Therefore, the risk-benefit ratio for using quinine/quinidine in the treatment of cramps in cirrhosis is unfavorable.

Eperisone hydrochloride 

Eperisone hydrochloride is a centrally acting muscle relaxant that appears to suppress sympathetic stimulation in skeletal muscle.44 Kobayashi et al7 treated 21 cirrhotic patients who reported having cramps more than once weekly in an open-label study with eperisone hydrochloride (150–300 mg) daily for 8 weeks. A complete disappearance of symptoms was found in 11 patients (61%), with decreased frequency in 6 patients (33%) and 1 patient with no change in symptoms. Adverse effects included epigastric discomfort, fatigue, and dizziness. Although there did appear to be a decrease in cramp frequency with treatment, the study was not blinded, there were significant side effects, and no long-term follow up data are available.

Energy Metabolism


Three small open-label studies have evaluated taurine as a treatment for muscle cramps in cirrhosis. In the first study, 12 nonalcoholic cirrhotic patients were given 6 g taurine 3 times daily for 4 weeks.23 Eight patients had complete resolution of cramps, and 4 patients had a significant decrease in cramp severity by 1 month. No adverse effects were observed. In a second study, 35 cirrhotic patients were treated with 3 g taurine daily for 4 weeks. Twenty-five patients (71.4%) had significant improvement in cramps, with 13 (37.1%) having complete disappearance of symptoms. A third study by Yamamoto et al28 extended the prior studies by comparing plasma taurine concentrations in 15 cirrhotic patients with cramps and 13 without cramps. Plasma taurine concentrations were significantly lower in the cirrhotic patients with cramps. Nine of the cirrhotic patients with cramps were given 3 g taurine daily for 4 weeks, and all had increased plasma taurine levels and reported significant improvement in symptoms, with 6 (67%) reporting complete resolution. No adverse effects were reported. These encouraging studies support that taurine may be a useful agent to treat muscle cramps in cirrhotic patients, particularly in those with low plasma taurine levels. However, larger double-blind, placebo-controlled studies are needed to confirm these findings.

Branched-chain amino acids 

Administration of branched-chain amino acids (isoleucine, leucine, and valine) in cirrhosis has been reported to improve serum albumin levels, increase taurine production, and possibly decrease progression of liver disease.45, 46, 47 Two studies have explored the possibility that branched-chain amino acid supplementation might also decrease the frequency of muscle cramps in patients with cirrhosis. Sako et al48 treated 8 patients in an open-label study with nocturnal branched-chain amino acid supplements for 3 months and found a significant increase in serum albumin levels and a significant decrease in frequency of cramps relative to pretreatment values (7.4 ± 2 to 0.3 ± 0.5 times/week, P < .0001). Hidaka et al49performed a small multicenter randomized study in 37 patients that compared daytime and nocturnal branched-chain amino acid supplementation for 3 months. The frequency of muscle cramps significantly decreased in both groups (P = .004), and no adverse effects were reported. These preliminary studies suggest that branched-chain amino acid supplementation may be an effective treatment for muscle cramps in cirrhosis.

Plasma Volume, Electrolytes, and Zinc 

Human albumin 

A single small crossover study has reported the use of intravenous albumin for treatment of muscle cramps in cirrhosis.9Twelve patients with compensated liver disease were given placebo or 100 mL 25% human albumin solution intravenously once weekly for 4 weeks. Compared with placebo administration, albumin significantly decreased cramp frequency (2.5 ± 2.9 vs 6.2 ± 2.5, P < .001) and also decreased PRA and improved MAP. These findings suggest that intravenous albumin may decrease cramps in cirrhosis, possibly by increasing intravascular plasma volume. From a practical perspective, the cost and requirement for intravenous access to deliver albumin limit feasibility as a therapy.

Electrolytes and zinc 

Serum electrolyte concentrations do not differ in cirrhotic patients with and without cramps. Therefore, studies have not focused on electrolyte replacement as a treatment for cramps. Empiric replacement of low serum electrolyte concentrations in cirrhotic patients with cramps is common, although whether this improves symptoms is unknown. Zinc has been used as empiric treatment for muscle cramps in cirrhosis.50 In a small study of 12 patients with low serum zinc concentrations (<70 μg/dL), oral zinc sulfate 220 mg twice daily for 12 weeks significantly decreased cramp frequency and increased serum zinc concentrations (40 ± 4.09 vs 63.8 ± 5.11 μg/dL, P = .0001). One patient reported mild diarrhea as an adverse effect. A subsequent study found low serum zinc concentrations in cirrhotic patients relative to healthy controls but no difference in levels between cirrhotic patients with and without cramps.10 These studies raise the possibility that zinc supplementation may be beneficial in cirrhotic patients with low serum zinc concentrations, but more data are needed.

Approach to the Cirrhotic Patient With Cramps 

In patients with cirrhosis who present with muscle pain, a careful history should be obtained to differentiate cramps (spontaneous, chronic, and often nocturnal) from other causes of pain (Figure 2). In particular, new-onset persistent muscle pain should trigger consideration of other diagnoses such as rhabdomyolysis, myositis, or acute kidney injury for which laboratory tests to assess electrolytes and other parameters would be appropriate. A standardized cramp questionnaire may be useful to define the presence and severity of cramps and in assessing the effectiveness of treatments (Figure 3).11, 51 In those found to have cramps, consideration of etiologies other than cirrhosis should be contemplated (Table 2). Serum electrolyte concentrations are frequently measured and, when low, repleted. When cramps related to cirrhosis are present and are clinically significant, an attempt at treatment is reasonable. Although large controlled trials are lacking, the use of over-the-counter, inexpensive agents with favorable side effect profiles (branched-chain amino acids, taurine, and vitamin E) may be considered. Branched-chain amino acids and taurine may have the greatest potential benefit on the basis of effects on proposed mechanisms for cramps and on possible improvement in nutritional parameters. Other treatments as outlined previously are not currently recommended because of ineffectiveness, expense, and/or the risk of side effects.

Figure 2.  Approach to the cirrhotic patient with cramps. CK, creatinine kinase; CRP, C-reactive protein; CQ, cramp questionnaire; EMG, electromyogram; ESR, erythrocyte sedimentation rate.


Figure 3.  Cramp Questionnaire. Clinically significant cramp (frequency of cramps/week × severity of cramps) >12.



Muscle cramps in patients with liver disease are common and are associated with a negative impact on QOL. Although a number of mechanisms for cramps in liver disease have been postulated and have been targeted by medical therapies, a clear picture of the causal events has not emerged. Several agents have shown benefit in small uncontrolled studies, although large randomized controlled trials are lacking. Treatments such as branched-chain amino acids and taurine may have the greatest potential benefit because they target proposed mechanisms and may also improve nutritional status.