FDA and Health Canada: Working Together for an Efficient Pathway for Drug Applications

Posted on January 31, 2014 by FDA Voice

By:  Robert Yetter, PhD

At FDA, we work closely with national regulatory agencies around the world on issues relating to the safety, efficacy and availability of medical products. An exciting example of such collaborative efforts is the Common Electronic Submissions Gateway (or CESG), an outcome of the US-Canada Regulatory Cooperation Council (RCC). Through a cooperative research and development agreement, FDA worked with our counterparts in Health Canada, to share technology that will make it more efficient for industry to submit applications to both the U.S. and Canada for the approval of pharmaceutical and biological products. A common infrastructure would enable industry to submit to both countries using the same electronic format for technical documents.

The RCC Initiative was announced in February 2011 by President Barack Obama and Prime Minister Stephen Harper. Its goals are to promote economic growth, job creation and benefits to consumers and businesses through increased regulatory transparency and coordination. The electronic submissions gateway is one such project designed to meet those goals.

So just what is this gateway? It’s an electronic “post office” that uses secure Internet connections to receive electronic versions of medical product applications and related documents from industry sponsors seeking regulatory approval. The technology was developed under contract, and implementation at FDA was led by the Center for Biologics Evaluation and Research.  FDA’s Electronic Submissions Gateway (ESG) has been in operation since 2006. It has now been modified to accommodate submissions from both Canada and the U.S. using the same interface and technology, and subsequently sending those submission transmissions to one or both regulatory authorities.

The collaboration on the Common Electronic Submissions Gateway has the potential to yield long-term positive outcomes for both FDA and Health Canada. The collaboration continues the work between the two regulatory partners to streamline both agencies’ submission requirements while maintaining consistency in regulatory requirements. It could also lead to cost reductions for regulated industry, which would not have to follow separate technical requirements for submission to the two countries.

We’re very proud of our work with Health Canada to make this technology accessible in a relatively short amount of time, going from concept to delivery in 26 months. This is yet another example of the steps FDA is taking as part of our Global Initiative, which envisions enhanced collaboration with our regulatory partners.

Robert Yetter, PhD, is the Associate Director for Review Management in FDA’s Center for Biologics Evaluation and Research

Source

What is the purpose of liver function tests?

Provided by Nursing Times

Practice educator

31 January, 2014

Author

Andrew Blann is a consultant at City Hospital, Birmingham, and senior lecturer in medicine, University of Birmingham.

ABSTRACT

Blann A (2014) Routine blood tests 2: what is the purpose of liver function tests? Nursing Times; 110: 6, 17-19.

The liver is the body’s largest single discrete organ. It has four major functions: metabolism and synthesis; excretion; storage; and the detoxification of potential poisons. These diverse functions mean that a single test does not give enough information to assess fully how the liver is functioning; at least five different liver function tests are required.

This article, part 2 in a four-part series, discusses the information on acute and chronic liver disease that these tests can provide, and how disease affects liver function.

• This article has been double-blind peer reviewed
• Figures and tables can be seen in the attached print-friendly PDF file of the complete article in the ‘Files’ section of this page

5 KEY POINTS

1. The liver plays an important role in synthesis, excretion, storage and detoxification
2. Its multiple metabolic and excretory functions mean disease of the liver can have serious consequences
3. The most obvious indication of liver disease is jaundice, a sign of high levels of bilirubin
4. Although the liver largely regenerates after damage, if damage is prolonged it loses its ability to do so
5. There are few clinical situations where a diagnosis can be made based on a single blood test

The liver, the largest single discrete organ in the body, has four main functions and plays a major part in many metabolic and excretory processes. Due to its multiple functions, liver disease has numerous consequences, many of which can be detected and monitored with blood tests known as liver functions tests (LFTs).

Main functions of the liver

Synthesis

The liver produces and exports many proteins and lipids into the blood, so reduced levels of certain proteins (such as albumin and clotting proteins) may indicate damage to the liver. The liver also synthesises fatty acids, triacylglycerols and cholesterol, but the levels of these lipids are not regarded as markers of liver function.

Excretion

When red blood cells die much is recycled, and what cannot be recycled is converted into bilirubin. Some bilirubin moves as bile into the gall bladder, while some immediately flows down the bile duct and through the duodenum, colouring the faeces brown.

The liver plays a significant role in removing excess nitrogen from the body through the production of urea.

Storage

Glucose is converted into the polysaccharide glycogen, which is stored in the liver. When there is too much glucose, it is converted into fat, which can be deposited in the liver and elsewhere. The liver also stores iron, vitamins, and copper.

Detoxification

In addition to synthesis and recycling, the liver has a role in detoxification. This includes metabolising plant, animal and fungal toxins (such as the fungal aflatoxin), as well as drugs and medication.

Liver disease

To carry out its diverse metabolic tasks, the liver uses several enzymes (Table 1). These help to link many of the liver’s functions to specific or non-specific tests; for many, the most obvious indication of liver disease is jaundice, a sign of high bilirubin levels.

Jaundice

Jaundice is a clear sign of liver disease, and is present when blood levels of bilirubin are so high (generally greater than 40mmol/L), that it enters the skin. This is most apparent in the sclera (white) of the eye. Jaundice is also called icterus and can develop in three ways: haemolytic, following red cell destruction; damage to liver cells; and failure to excrete bile, most likely due to obstruction.

At such high levels in the blood, this bilirubin finds its way to the kidney and into the urine, which becomes dark yellow and possibly orange/brown; this is an additional important clinical sign.

Cholestasis

This common condition is caused by obstruction or stenosis of the bile duct by, for example, gallstones or a tumour. This prevents the liver and biliary system from excreting bile, leading to obstructive cholestasis.

Inflammatory cholestasis occurs when inflammation of the bile duct prevents bile from passing into the duodenum; the liver continues to generate bile, which fills the gall bladder leading to congestion. Once the gall bladder is full, bile cannot leave the liver and it passes into the blood causing jaundice. A further sign of cholestasis is a change in the colour of the faeces from brown to grey, a likely indication that bile is not entering the intestines.

Cirrhosis

If damaged, such as after a viral infection or exposure to a poison, the liver has a remarkable capacity to regenerate.

However, if the damage is prolonged, for example due to a chronic infection, the renewal processes may be unable to continue regenerating functioning liver cells, leading to fibrous tissues being deposited instead. Cirrhosis can be the end result of several lengthy pathological processes, including: autoimmune diseases; chronic hepatitis virus B infection; longstanding biliary obstruction; and alcohol misuse.

Eventually, the loss of functioning cells may lead to chronic liver failure, and possibly liver cancer.

Ascites

Ascites is the excessive accumulation of plasma-like fluid in the peritoneal cavity. In up to 75% of patients, it is a consequence of advanced cirrhosis leading to portal hypertension. Other causes include heart failure, cancer and inflammation (Senousy and Draganov, 2009).

Cancer

The primary malignancy of the liver is hepatocellular carcinoma (HCC). According to Cancer Research UK (2014), it makes up 1.3% of cancers, and well over 3,000 new cases arise each year.

HCC is also sometimes referred to as hepatoma, but technically this means a mass within the liver that may not necessarily be a malignancy.

The vast majority of liver cancer occurs in the liver cells (hepatocytes) themselves; cancer of the bile ducts - cholangiocarcinoma - is less common.

The main causes of liver cancer are chronic viral infection (hepatitis B and C) and long-term alcohol misuse. The key laboratory test for this type of cancer is alpha-fetoprotein (AFP); however, if the liver is the site of a secondary cancer (metastasis), AFP will be negative.

Fatty liver (steatosis)

Fat is effective for storing energy, and large deposits can be found in various parts of the body, such as around the heart and liver.

However, if fat intake is excessive, in certain rare metabolic conditions and if alcohol is misused, fat starts to be stored in the liver. In the absence of alcohol misuse, this leads to non-alcohol fatty liver disease, which in its mild form is described as steatosis.

The damage caused by lipid overloading leads to hepatocellular damage, inflammation and fibrosis, and the disease transforms to non-alcoholic steatohepatitis (NASH). This progresses to cirrhosis in about 5-8% of patients within five years, and may be complicated by hepatocellular carcinoma and liver failure (Adams and Angulo, 2006). NASH may be secondary to a number of conditions including diabetes, impaired fasting glycaemia, malnutrition, hypertension and obesity.

There are many other less common liver diseases, some of which are in Table 2.

Liver function tests

The interpretation of LFTs is complicated: there are few examples of clinical situations where a single blood test is sufficiently reliable to diagnose a precise disease, so practitioners need to gather as much information as possible before making a clinical judgement.

Aspartate aminotransferase (AST) and alanine aminotransferase (ALT)

Increased levels of these enzymes are traditionally seen as markers of damage to liver cells, which could have any one of several causes including infective agents, autoimmune disorders and toxins.

Infections with microbial pathogens all cause an increase in AST and/or ALT, although the latter is better for monitoring viral activity in chronic hepatitis B and C as it is released from damaged hepatocytes more easily.

AST and ALT are found in many non-liver cells, including skeletal and cardiac muscle, so raised levels following a heart attack do not necessarily imply liver disease. Similarly, raised AST is commonly found in haemolytic anaemia as this enzyme is present in red blood cells. Another blood test, lactate dehydrogenase (LDH), can be helpful in confirming the diagnosis of haemolytic anaemia.

Many drugs and toxins can also raise AST and/or ALT levels. These include alcohol, industrial solvents and cholesterol-lowering drugs of the statin class.

Bilirubin

This has been described as the only true LFT, as clearing this potential toxin is a major liver function. Although the most common non-hepatic cause of raised bilirubin is excessive haemolysis, true liver disease, such as Wilson’s disease, may also cause red blood cell destruction and anaemia.

Bilirubin in neonates deserves special mention. The neonatal liver is under-developed and shortly after birth may not be mature enough to process its own bilirubin. This may lead to hyperbilirubinaemia and jaundice, which should normalise within 2-3 days after birth as the liver matures.

Alkaline phosphatase (ALP)

The most common cause of raised ALP is obstruction of the bile duct or its tributaries (cholestasis), commonly caused by gallstones. Primary biliary cirrhosis and pancreatic malignancy also cause an increase in ALP levels.

The major non-hepatic source of plasma ALP is bone, and raised levels are found in the absence of liver disease in patients with metabolic bone disease, such as Paget’s disease. Increased ALP may also be present in a primary or secondary bone cancer (typically metastases from prostate and breast cancer).

Gamma-glutamyl transpeptidase (gamma-GT)

There are numerous hepatic and non-hepatic causes of raised gamma-glutamyl transpeptidase (gamma-GT); it is often present in: cirrhosis or hepatitis; haemochromatosis; HCC; and secondary cancer.

Gamma-GT levels are also influenced by several commonly used drugs, such as phenytoin, barbiturates, carbamazepine and alcohol, which make this test less reliable.

Comparing the LFTs

In paracetamol poisoning, AST needs to be considered alongside bilirubin in assessing prognosis using serial results, perhaps over a period of a week.

If the AST and bilirubin fall in parallel, it suggests hepatic recovery and good prognosis. However, a falling AST with a rising bilirubin indicates critical loss of hepatocytes and a poor prognosis.

The ratio of the aminotransferases can be helpful. An AST:ALT ratio greater than 2:1 implies alcohol misuse because of the release of mitochondrial AST due to damage from alcohol metabolites.

A rise in AST may also be compared with rises in ALP; if AST is higher, this is suggestive of hepatitis. ALP and gamma‑GT often rise and fall together in many conditions, but ALP is the better marker of biliary and bone disease and GGT of alcoholic disease.

Table 3 gives a synopsis of the LFTs.

● This article was adapted from: Blann AD (2013) Routine Blood Tests Explained. Keswick: M&K Update.

References:

Adams LA, Angulo P (2006) Treatment of non-alcoholic fatty liver disease. Postgraduate Medical Journal; 82, 315-322.

Cancer Research UK (2014) Twenty Most Common Cancers.

Senousy BE, Draganov PV (2009) Evaluation and management of patients with refractory ascites. World Journal of Gastroenterology; 15, 67-80.

Source

Abbvie completes largest phase III program of an all-oral, interferon-free therapy for the treatment of hepatitis C genotype 1

- NINETY-NINE PERCENT SVR(12) RATES WITH AND WITHOUT RIBAVIRIN IN CERTAIN PATIENT TYPES

- EVEN IN DIFFICULT-TO-TREAT PATIENTS (CIRRHOTIC PATIENTS) ACHIEVED 92-96 PERCENT SVR(12) RATES

- ABBVIE EXPECTS U.S. LAUNCH IN 2014

Jan 31, 2014

NORTH CHICAGO, Ill., Jan. 31, 2014 /PRNewswire/ -- AbbVie (NYSE: ABBV) announced the completion of its phase III clinical program and released results of four additional studies designed to assess AbbVie's investigational all-oral, interferon-free therapy with and without ribavirin (RBV) in patients with chronic genotype 1 (GT1) hepatitis C virus (HCV) infection. These results described below confirm previously reported AbbVie data and further demonstrate high sustained virologic response rates 12 weeks post treatment (SVR₁₂) and tolerability in these GT1 patients.

AbbVie Phase III Clinical Program Results

Study	Patients	Treatment Regimen	SVR12
PEARL-II (12 weeks)	GT1b treatment-experienced (N=179)	AbbVie regimen + RBV (n=88)	97% (85/88)
		AbbVie regimen only (n=91)	100% (91/91)
PEARL-III (12 weeks)	GT1b treatment-naive (N=419)	AbbVie regimen + RBV (n=210)	99% (209/210)
		AbbVie regimen only (n=209)	99% (207/209)
PEARL-IV (12 weeks)	GT1a treatment-naive (N=305)	AbbVie regimen + RBV (n=100)	97% (97/100)
		AbbVie regimen only (n=205)	90% (185/205)
TURQUOISE-II (12 & 24 weeks)	GT1 treatment-naive  and treatment-experienced with  compensated cirrhosis (N=380)	AbbVie regimen + RBV, 12 weeks (n=208)	92% (191/208)
		AbbVie regimen + RBV, 24 weeks (n=172)	96% (165/172)
SAPPHIRE-I (12 weeks)	GT1 treatment-naive (N=631)	AbbVie regimen + RBV (n=473)	96% (455/473)
SAPPHIRE-II (12 weeks)	GT1 treatment-experienced (N=394)	AbbVie regimen + RBV (n=297)	96% (286/297)

"The outcomes of AbbVie's comprehensive phase III studies in 2,300 patients across 25 countries demonstrate how our investigational regimen performs across a broad spectrum of genotype 1 patients, including those with compensated liver cirrhosis," said Scott Brun, M.D., vice president, pharmaceutical development, AbbVie. "The high rates of response and tolerability of our regimen, coupled with the low rates of discontinuation are promising."

The AbbVie investigational regimen consists of the fixed-dose combination of ABT-450/ritonavir (150/100mg) co-formulated with ABT-267 (25mg), dosed once daily, and ABT-333 (250mg) with or without ribavirin (weight-based), dosed twice daily. The combination of three different mechanisms of action interrupts the HCV replication process with the goal of optimizing SVR rates across different patient populations. In May of 2013, AbbVie's regimen with and without ribavirin for HCV GT1 was designated as a Breakthrough Therapy by the U.S. Food and Drug Administration (FDA). AbbVie is on track to begin major regulatory submissions early in the second quarter of 2014. AbbVie will disclose detailed study results at future scientific congresses and in publications.

About Study M13-389 (PEARL-II)
PEARL-II is a global, multi-center, randomized, open-label, controlled study to evaluate the efficacy and safety of 12 weeks of treatment with AbbVie's regimen with and without ribavirin in non-cirrhotic, GT1b HCV-infected, treatment-experienced adult patients.

The study population consisted of 179 GT1b treatment-experienced patients with no evidence of liver cirrhosis: 91 patients randomized to the regimen without ribavirin for 12 weeks, and 88 patients randomized to the regimen with ribavirin for 12 weeks. In the ribavirin-free arm, 100 percent (n=91/91) of patients achieved SVR₁₂, while 97 percent (n=85/88) achieved SVR₁₂ in the ribavirin-containing arm.

The most commonly reported adverse events were fatigue and headache. Discontinuations due to adverse events were reported in none of the patients in the ribavirin-free arm and two (2 percent) patients in the ribavirin-containing arm. There were no patients in either arm of the study that experienced virologic relapse or breakthrough.

About Study M13-961 (PEARL-III)
PEARL-III is a global, multi-center, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of 12 weeks of treatment with AbbVie's regimen with and without ribavirin in non-cirrhotic, GT1b HCV-infected, treatment-naive adult patients.

The study population consisted of 419 GT1b treatment-naive patients with no evidence of liver cirrhosis: 209 patients randomized to the regimen without ribavirin for 12 weeks, and 210 patients randomized to the regimen with ribavirin for 12 weeks. Following 12 weeks of treatment, 99 percent receiving the regimen without ribavirin (n=207/209) and 99 percent receiving the regimen with ribavirin (n=209/210) achieved SVR₁₂.

The most commonly reported adverse events were headache and fatigue. No patient discontinued study drug due to adverse events. Virologic relapse or breakthrough was noted in none of the patients receiving the regimen without ribavirin and 0.5 percent of patients receiving the regimen with ribavirin.

About Study M14-002 (PEARL-IV)
PEARL-IV is a global, multi-center, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of 12 weeks of treatment with AbbVie's regimen with and without ribavirin in non-cirrhotic, GT1a HCV-infected, treatment-naive adult patients.

The study population consisted of 305 GT1a treatment-naive patients with no evidence of liver cirrhosis: 205 patients randomized to the regimen without ribavirin for 12 weeks, and 100 patients randomized to the regimen with ribavirin for 12 weeks. Following 12 weeks of treatment, 90 percent of patients receiving the regimen without ribavirin (n=185/205) and 97 percent receiving the regimen with ribavirin (n=97/100) achieved SVR₁₂.

The most commonly reported adverse events were fatigue, headache and nausea. Discontinuations due to adverse events were reported in two (1 percent) patients receiving the regimen without ribavirin and no patients in the ribavirin-containing arm. Virologic relapse or breakthrough was noted in 8 percent of patients receiving the regimen without ribavirin and 2 percent of patients receiving the regimen with ribavirin.

About Study M13-099 (TURQUOISE-II)
TURQUOISE-II is the first phase III study completed exclusively in GT1 cirrhotic patients investigating an all-oral, interferon-free regimen. It is a global, multi-center, randomized, open-label study evaluating the efficacy and safety of 12 or 24 weeks of treatment with AbbVie's regimen with ribavirin in cirrhotic, GT1a and GT1b HCV-infected, treatment-naive and treatment-experienced adult patients.

The study population consisted of 380 GT1a and GT1b, treatment-naive and treatment-experienced patients with compensated cirrhosis: 208 patients randomized to the regimen with ribavirin for 12 weeks, and 172 patients randomized to the regimen with ribavirin for 24 weeks. Following 12 weeks of treatment, 92 percent of patients (n=191/208) achieved SVR₁₂. Following 24 weeks of treatment, 96 percent of patients (n=165/172) achieved SVR₁₂.

The most commonly reported adverse events were fatigue, headache and nausea. Discontinuations due to adverse events were reported in four (2 percent) patients receiving the regimen with ribavirin for 12 weeks and four (2 percent) patients in the 24-week arm. Virologic relapse or breakthrough was noted in 6 percent of patients in the 12-week arm and 2 percent in the 24-week arm.

Additional information about AbbVie's phase III studies can be found on www.clinicaltrials.gov.

Globally, approximately 160 million people are chronically infected with hepatitis C[1]. AbbVie's multinational HCV program is the largest all-oral, interferon-free clinical program in GT1 patients being conducted to date[2]. GT1 (with subtypes 1a and 1b) is the most prevalent genotype worldwide.

AbbVie's HCV Development Program
The AbbVie HCV clinical development program is intended to advance scientific knowledge and clinical care by investigating an interferon-free, all-oral regimen with and without ribavirin with the goal of producing high SVR rates in as many patients as possible, including those that typically do not respond well to treatment, such as previous non-responders to interferon-based therapy or patients with advanced liver fibrosis or cirrhosis.

ABT-450 was discovered during the ongoing collaboration between AbbVie and Enanta Pharmaceuticals (NASDAQ: ENTA) for HCV protease inhibitors and regimens that include protease inhibitors. ABT-450 is being developed by AbbVie for use in combination with AbbVie's other investigational medicines for the treatment of HCV.

Safety Information for Ribavirin and Ritonavir
Ribavirin and ritonavir are not approved for the investigational use discussed above, and no conclusions can or should be drawn regarding the safety or efficacy of these products for this use.

There are special safety considerations when prescribing these drugs in approved populations.

Ritonavir must not be used with certain medications due to significant drug-drug interactions and in patients with known hypersensitivity to ritonavir or any of its excipients.

Ribavirin monotherapy is not effective for the treatment of chronic hepatitis C virus and must not be used alone for this use. Ribavirin causes significant teratogenic effects and must not be used in women who are pregnant or breast-feeding and in men whose female partners are pregnant. Ribavirin must not be used in patients with a history of severe pre-existing cardiac disease, severe hepatic dysfunction or decompensated cirrhosis of the liver, autoimmune hepatitis, hemoglobinopathies, or in combination with peginterferon alfa-2a in HIV/HCV co-infected patients with cirrhosis and Child-Pugh score ≥ 6.

See approved product labels for more information.

About AbbVie
AbbVie is a global, research-based biopharmaceutical company formed in 2013 following separation from Abbott Laboratories. The company's mission is to use its expertise, dedicated people and unique approach to innovation to develop and market advanced therapies that address some of the world's most complex and serious diseases. AbbVie employs approximately 25,000 people worldwide and markets medicines in more than 170 countries. For further information on the company and its people, portfolio and commitments, please visit www.abbvie.com. Follow @abbvie on Twitter or view careers on our Facebook or LinkedIn page.

Forward-Looking Statements
Some statements in this news release may be forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995. The words "believe," "expect," "anticipate," "project" and similar expressions, among others, generally identify forward-looking statements. AbbVie cautions that these forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those indicated in the forward-looking statements. Such risks and uncertainties include, but are not limited to, challenges to intellectual property, competition from other products, difficulties inherent in the research and development process, adverse litigation or government action, and changes to laws and regulations applicable to our industry.

Additional information about the economic, competitive, governmental, technological and other factors that may affect AbbVie's operations is set forth in Item 1A, "Risk Factors," in AbbVie's 2012 Annual Report on Form 10-K/A, which has been filed with the Securities and Exchange Commission.

AbbVie undertakes no obligation to release publicly any revisions to forward-looking statements as a result of subsequent events or developments, except as required by law.

[1] Lavanchy D. Evolving epidemiology of hepatitis C virus. Clin Microbiol Infect. 2011; 17(2):107-15.  
[2] Comparison based on review of data from www.clinicaltrials.gov for phase 3a programs of Gilead, BMS and BI as of November 15, 2013.

SOURCE AbbVie

For further information: Media: Elizabeth Hoff, +1 (847) 935-4236, elizabeth.hoff@abbvie.com , or Javier Boix, +1 (847) 937-6113, javier.boix@abbvie.com, Investor Relations: Elizabeth Shea, +1 (847) 935-2211, elizabeth.shea@abbvie.com

Source

Tips for Managing Symptoms Associated with HCV

David Novak
January 30, 2014

Based on research from the World Health Organization (WHO), each year 3 to 4 million people are infected by hepatitis C virus, or HCV, and more than 350,000 die every year because of this chronic disease. Fortunately, due to the introduction of direct-acting antivirals, the treatment for HCV has been dramatically improved. However, some of these medications have troublesome side effects that can interfere with normal daily activities. Here are simple and practical tips that can help in managing and reducing these side effects:

Tiredness and weakness

The majority of people with chronic hepatitis C or HCV will experience extreme tiredness, especially during treatment. Severe fatigue may develop in patients that don’t show any signs of changes, or perhaps small little changes in the liver. The feeling of tiredness and weakness is usually accompanied by a total lack of energy, which can affect daily activities. Peginterferon injections, which is an antiviral drug treatment for HCV, are also known to cause fatigue, which usually worsens 1-2 days after injections. It is best to plan ahead on when is the best time to receive this treatment, and make sure that you’ll be able to rest the next day. It is also important to remain physically active if you’re able, but in some cases it is best to conserve your energy, especially during treatment or if you have advance liver failure.

Pain and soreness

Flu-like symptoms -- such as chills, fever, muscle soreness and joint pain -- are common with HCV. Peginterferon injections can also cause flu-like symptoms that usually subside after two to three weeks of taking the drug. Some choose to take peginterferon injections before bedtime so that they can sleep through the discomfort; however, these same injections can cause insomnia, and in those instances, this tactic isn’t very effective. Drinking plenty of fluids can help in keeping your body hydrated and potentially aid in easing some of the symptoms. There are also medications that can help in managing the pain, but it is best to consult your doctor to avoid further complications.

Eating problems

Loss of appetite is fairly common among patients undergoing HCV treatment, so it’s essential for them to consume highly nutritious foods to avoid serious weight loss and other complications. Eating smaller but frequent meals throughout the day, and drinking clear fruit juices can help in adding extra calories. Add variety to the food choices and take time to make your meals appealing and tasty. Nausea is also one of the side-effects associated with HCV treatment and it can affect the appetite. Make sure to keep track of foods that can cause nausea, so they can be avoided in the future.

Avoid skipping meals because an empty stomach can also trigger nausea. Try to incorporate ginger in your meal because this spice is known to be helpful in keeping nausea at bay. If needed, you can also ask your doctor about anti-nausea medication.

Skin conditions

Almost every patient undergoing HCV treatment may develop some type of skin condition. Porphyria cutanea tarda is one of them, and it’s characterized by fluid-filled blisters on the hands and other areas when exposed to sunlight. Though it’s incurable, it can still be managed through medication. Blotchy skin rashes are another one of the symptoms, actually caused by cryoglobulinemia, which is an autoimmune disorder commonly associated with HCV. Medications are also available to help in suppressing the immune system that usually triggers this condition. Hair loss, or alopecia, is also a side effect caused by peginterferon injections. This repercussion is only temporary, and hair usually grows back when the treatment is over.

Bleeding

In severe cases of HCV, vomiting of blood and bloody bowel movement can be experienced, and these conditions are also linked to cirrhosis and liver failure. Medications can help with constricting open varices, and in severe cases, endoscopic surgery can be performed. Another condition associated with HCV is thrombocytopenia, wherein the body produces a low platelet count. This can be a very serious condition, especially for those with bleeding disorders, so it’s best to consult your doctor if bleeding occurs.

Mood changes

Most HCV patients experience depression, irritability, insomnia and difficulty concentrating. Depression is an emotional state wherein the person feels terribly sad, and this state can last for several weeks or months. There are several antidepressant drugs available to reduce the feeling of depression. Psychological therapy is also proven effective in mood improvement. Meditative exercises such as tai chi and yoga can also help in calming the nerves and relieving stress.

  David Novak’s byline has appeared in newspapers and magazines around the world. He’s an avid health enthusiast, and frequently is featured in regional and national health publications. He is also a weekly writer for Healthline. To visit his other stories on Healthline, visit http://www.healthline.com/.

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Common Conditions Associated with Hepatitis C

David Novak
January 30, 2014

Hepatitis C is a contagious liver condition caused by infection with hepatitis C virus. It is also the most common form of viral hepatitis. Hepatitis C virus can be transmitted through needles that are contaminated, as well as through blood transfusions. Severity of illness can range from mild illness, which could last for several weeks, to serious lifelong condition. According to the World Health Organization or WHO, about 150 million people are chronically infected with hepatitis C virus, and more than 350,000 people die every year because of hepatitis C-related conditions, such as cirrhosis and other liver diseases. Here are several common conditions that are associated with hepatitis C virus:

Cryoglobulinemia

Cryoglobulinemia is one of the most associated diseases with Hepatitis C. It is a medical condition caused by abnormal proteins called cryoglobulins, which come from the simulation of lymphocytes, or white blood cells, by hepatitis C virus. Cryoglobulinemia is usually characterized by joint pain or swelling, raised purple skin rash, nerve pain and increased sensitivity to weather changes. Cryoglobulinemia can be diagnosed by a special laboratory test to detect cryoglobulins in the blood. Tissue biopsies can also help the diagnosis by uncovering inflammation of small blood vessels.

Cirrhosis

Cirrhosis is a complication of the liver, resulting in loss of liver cells and irreversible scarring of the liver. It is usually characterized by redness of the skin caused by dilated small blood vessels, shrinking of the muscles, bleeding from enlarged veins in the digestive tract, nose bleeds, weight loss and damage to the brain and nervous system. A combination of tests will help in diagnosing cirrhosis. This includes a physical exam and records of medical history.

Autoimmune Thyroid Dysfunction

There are two conditions of thyroid dysfunction associated with hepatitis C. One is hyperthyroidism, wherein the thyroid gland becomes overactive and secretes an excessive amount of hormones. Symptoms include nervousness, heart racing, anxiety, thinning of the skin and muscular weakness. Another condition is hypothyroidism, wherein the thyroid gland doesn't produce enough hormones, resulting in fatigue, weight gain, poor memory and concentration, hair loss and peripheral edema.

Autoimmune Thrombocytopenic Purpura

This autoimmune disorder is caused by low levels of platelets, which are cells that help the clotting of blood. The immune system produces antibodies that mistakenly destroy platelets, resulting in spontaneous formation of bruises, bleeding and menorrhagia. Autoimmune thrombocytopenic purpura, or ATP, is diagnosed by a full blood count, wherein low platelet count can be observed.

Leukocytoclastic Vasculitis

Leukocytoclastic vasculitis (LCV) is an immune system abnormality, which is characterized by inflammation of blood vessels. The actual cause of this disease is unknown, though it is associated with various infections such as hepatitis, cancers and rheumatic diseases. LCV can be diagnosed through laboratory testing of blood and body fluids. Organ function tests can also be done depending on the degree of the organ involvement.

Lichen Planus

This skin condition is a recurrent, itchy rash with unknown initial triggers. Lichen planus is characterized by shiny, reddish-purple spots on the skin, which can grow to rough, scaly plaques. Rashes can also develop in the lining of the mouth, lips and the lateral border of the tongue. This disorder is also known to affect women more frequently than men.

Those with extensive lichen planus disease appears to be more likely to have hepatitis C virus infection, though it is unclear if it is the main cause of the condition. It is also associated with different liver diseases.

Porphyria Cutanea Tarda

Porphyria cutanea tarda, or PCT, is the most common subtype of porphyria in which the skin shows several abnormalities when exposed to sunlight. It could result in scarring and blistering of skin, as well as onycholysis. Hepatitis C, HIV and estrogens are several environmental factors that can trigger PCT.

Non-Hodgkin’s Lymphoma

Patients with hepatitis C have a 20 to 30 percent higher risk of developing lymphoma, based on research done by the National Cancer Institute. Lymphoma is a type of cancer that affects lymphocytes, which is a white-blood cell generated by the immune system. This disease generally affects the lymphatic system, whose main function is to help the immune system in fighting off infections and diseases by filtering out viruses, bacteria and unwanted substances. Symptoms of non-Hodgkin’s lymphoma include unexplained weight loss, fever, swollen and painless lymph nodes, abdominal pain and itching of the skin.

  David Novak’s byline has appeared in newspapers and magazines around the world. He’s an avid health enthusiast, and frequently is featured in regional and national health publications. He is also a weekly writer for Healthline. To visit his other stories on Healthline, visit http://www.healthline.com/

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Taming the Dragon

by Opiferum
January 30, 2014

The phrase “chasing the dragon” means to inhale the vapour of heated morphine, heroin, oxycodone or opium that has been placed on a piece of foil. On the other hand, the phrase “silent” or “yellow dragon” refers to the hepatitis C virus (HCV). Small difference, big coincidence? After all, hepatitis C is so often cited as a disease that results from opioid drug use, one could easily be mistaken for thinking there is a connection! In Chinese medicine, the liver is represented by a dragon that is said to store anger. This seems like a more plausible explanation, however, it also illustrates how the same word can mean very different things depending on the context. Even though the “dragon” with respect to smoking drugs has no connection to the hepatitis C virus, it just demonstrates how the words used with regard to hepatitis C can also play upon very different meanings depending on the context. Sometimes, the result is not helpful for reducing HCV-related stigma. Perhaps this is why we not only need to “slay the dragon” with medical treatment, but also start “taming the dragon” with language instead.

Leading up to World Aids Day last year, The Stigma Project released some fantastic projects that promoted the elimination of stigma of HIV & AIDS on a global scale, “through awareness, art, provocation, education and by inspiring a spirit of living HIV Neutral.” This is something that desperately needs to be achieved within the hepatitis C affected community, too. One of the key lessons given by The Stigma Project is how to refer to a person that lives with HIV. Instead of saying that a person is “HIV positive”, for example, the non-discriminating way in which to do this is to refer to someone as “living with HIV”. Haven’t really thought about when you refer to in yourself as hepatitis C positive? Don’t worry, you have probably been labelled as “hep C positive” for so long by doctors or family, that it’s kind of hard to ignore (or deny). However, you have the right NOT to feel that your disease is what makes you who you are, simply because of living with it. Nobody living with the hepatitis C virus needs to carry the “hep C positive” label, which in itself instantly sends to other a fear inducing message that, “I am infectious”. Furthermore, describing a person as “living with hepatitis C” is indeed a more accurate description. After all, it’s not as if people living with cancer are called “cancer positive” or “cancerous”.

Let’s look at some other commonly used terms within HCV-related literature that also adds to unnecessary instances of stigma inducing concepts. The most harmful include “drug abuse” and “drug addict”. Whilst there is no arguing that hepatitis C is an infection that grossly affects people that inject drugs, it is simply unforgiving to refer to “drug abuse” as a way in which hepatitis C is spread. Not sure why? Well, it’s quite simple, really: not all drug use is abuse, and not all drug use is high-risk. As well, just the reference to “drug abuse” with respect to HCV transmission links a person’s conscious to the sordid stereotype image our society associates with a “drug addict” or (even worse) a “junkie”. More importantly, the term “drug abuse” makes no distinction between licit and illicit drug use. Rather, referring to “drug abuse” in relation to hepatitis C always affiliates the disease with illicit drug use: it creates a division based upon ideas related to “lawful” and “unlawful”. As well, it makes the assumption that people that inject drugs must also share needles - by default. With respect to HIV/AIDS education, the distinction between “safe” and “unsafe” sex is commonly accepted. It only seems fair to distinguish between “safe” and “unsafe” injecting drug use.

As well, when referring to “drug abuse” without a second-thought, the common perception is that only illicit drug use can fall under the umbrella of “drug abuse”. After all, how often do we hear the term “alcohol abuse” with respect to cirrhosis of the liver? Instead, we typically hear of “heavy” and “binge” drinking, or “alcoholism”. The terms are not used interchangeably, despite the fact they can all be classified as forms of “abuse” because of the short- and long-term effects. But because alcohol is a legal substance, “alcohol abuse” simply does not exist in our language because “abuse” carries with it a totally different moral discourse.

How successfully we can eliminate the stigma attached to hepatitis C and those that live with the virus is something we can definitely achieve by making better choices of our words. As the old saying goes, Think twice before you speak, because your words and influence will plant the seed of either success of failure in the mind of another. - Napoleon Hill (1883 - 1970)

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Mount Sinai researchers identify UHRF1 as oncogene driving liver cancer

PUBLIC RELEASE DATE: 30-Jan-2014

Contact: Laura Newman
laura.newman@mountsinai.org
212-241-9200
The Mount Sinai Hospital / Mount Sinai School of Medicine

Finding spurs R&D into epigenetic-modifying drugs for this lethal disease

This shows a 5-day old zebrafish expressing green fluorescent protein in hepatocytes (liver cells) to highlight the liver.

New York, NY – Patients with advanced hepatocellular (or liver) cancer have high mortality rates, with existing drugs demonstrating only a small, but significant survival advantage. By combining a zebrafish model of liver cancer with data from human tumors, researchers from the Icahn School of Medicine at Mount Sinai hope to identify potential genes of interest that can be targeted for new treatments for hepatocellular carcinoma, the most common form of liver cancer to develop from liver cells.

Using transgenic zebrafish as an emerging, powerful whole animal model for cancer gene discovery, in combination with cultured cells and data from human tumors, they found that a gene called UHRF1, which is highly expressed in many types of cancers, can cause liver cancer at an unprecedented rate and incidence – with tumors forming in 75% of fish within 20 days. Results from the study are published online in the journal Cancer Cell.

"This is the first time that UHRF1 has been shown to be sufficient on its own to cause any kind of cancer when it is highly expressed," said the study's senior investigator, Kirsten C. Sadler, PhD, Associate Professor Medicine in the Division of Liver Diseases and of Developmental and Regenerative Biology, and Director of the Zebrafish Research Facility at the Icahn School of Medicine at Mount Sinai. UHRF1 has generated a lot of interest because it is a central regulator of epigenome – which is a collection of reversible modifications to DNA and the DNA packaging proteins – that are important for deciding which genes are expressed and how the DNA is transmitted during cell division. The cancer cell epigenome is dramatically different from normal cells, and the field of cancer epigenetics is exploding because of the hope that these changes could be reversed, and thereby reverse the aggressive nature of cancer cells. "Down the road, we hope to develop drugs to target UHRF1 and thereby reset the cancer epigenome to activate anti-tumor mechanisms and halt liver cancer.," added Dr. Sadler.

\UHRF Levels Important in Human Liver Cancers, Too

When the team analyzed patient-derived liver tumors, they found that high levels of the UHRF1 were also found there, too. Most strikingly, the changes in gene expression caused by high UHRF1 levels in zebrafish were reflected in the human tumors expressing high UHRF1 levels. This points to similar mechanisms underlying UHRF1-driven liver tumor formation in both species. One of these is the ability of the cancer-prone cells to bypass the tumor suppressive mechanisms that are activated in most cells when they receive a cancer-causing stimulus.

Cellular senescence is one such mechanism, and this study found that tumors associated with UHRF1 levels in both fish and humans only those cells that could escape senescence were the ones that could go on to form the tumors. This lays the groundwork to use this model to test new therapies that would target UHRF1 to re-activate the senescence program and halt cancer formation.

Dr. Sadler pointed to several advantages of using zebrafish in preclinical liver disease research. Zebrafish reproduce rapidly and abundantly, they are translucent until about three weeks of age, enabling researchers to directly visualize tumor growth, and the cells in the liver function similarly to those in humans. Zebrafish are also inexpensive to raise, making this study uniquely powerful, as they analyzed nearly 300 fish for tumors in this study– a scope that would be extremely costly using traditional mammalian cancer models.

UHRF1 is overexpressed in around 40%-50% hepatocellular cancers in humans and predict poor outcome. This overexpression is associated with poorer prognosis in terms of high recurrence rate and low term overall survival. "We have little to offer people in the setting of advanced disease – and this points to an entirely new direction," Dr. Sadler said. "It raises the hope that epigenetic drugs could be applied to liver cancer in the future."

Commenting on the research, Scott Friedman, MD, Dean for Therapeutic Discovery, and Fishberg Professor of Medicine, and Chief of the Division of Liver Diseases, at the Icahn School of Medicine at Mount Sinai, said: "Dr. Sadler's team has conducted a remarkable study that combines the power of the zebrafish model with state of the art genomic analysis of a devastating and poorly treated human cancer. This kind of comprehensive study not only uncovers a new approach to treating hepatocellular carcinoma, but also provides a vital roadmap to unlocking cancer's secrets more quickly and effectively."

The need for better treatments for hepatocellular cancer was underscored by Josep M. Llovet, MD, a study coauthor, and Professor of Medicine, and Director, Mount Sinai Liver Cancer Program. "The incidence of hepatocellular cancer is increasing worldwide and the median outcome at advanced stages with the sole effective molecule available, Sorafenib, is one year. Thus, identification of novel targets for HCC therapies are an unmet medical need. The current study points to the fact that UHRF1 is an oncogene driver and a potential target for therapies"

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Other researchers contributing to this research from the Icahn School of Medicine at Mount Sinai were Raksha Mudbhary, Yujin Hoshida, Yelena Chernyavskaya, Vinitha Jacob, M. Isabel Fiel, Xintong Chen, Kensuke Kojima, Swan Thung, Anja Lachenmayer, Kate Revill, Ravi Sachidananandam, and Josep M. Llovet. The research team also included investigators from Harvard Medical School's Brigham and Women's Hospital and the IDIBAPS- Hospital Clínic and Institucio Catalana de Recerca, in Barcelona Spain.

About Cancer Gene Discovery in Zebrafish

Researchers in the Liver Cancer Research Program at the Icahn School of Medicine at Mount Sinai use genetic approaches in live zebrafish and in cultured human cancer cells. They collaborate with translational researchers to exploit data from human tumors to identify novels targets for treating hepatocellular carcinoma.

About the Mount Sinai Health System

The Mount Sinai Health System is an integrated health system committed to providing distinguished care, conducting transformative research, and advancing biomedical education. Structured around seven member hospital campuses and a single medical school, the Health System has an extensive ambulatory network and a range of inpatient and outpatient services—from community-based facilities to tertiary and quaternary care.

The System includes approximately 6,600 primary and specialty care physicians, 12-minority-owned free-standing ambulatory surgery centers, over 45 ambulatory practices throughout the five boroughs of New York City, Westchester, and Long Island, as well as 31 affiliated community health centers. Physicians are affiliated with the Icahn School of Medicine at Mount Sinai, which is ranked among the top 20 medical schools both in National Institutes of Health funding and by U.S. News & World Report.

For more information, visit http://www.mountsinai.org. Find Mount Sinai on: Facebook: http://www.facebook.com/mountsinainyc Twitter @mountsinainyc YouTube:http://www.youtube.com/mountsinainy

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The impact of hepatitis C burden: an evidence-based approach

Aliment Pharmacol Ther. 2014 Jan 26. doi: 10.1111/apt.12625. [Epub ahead of print]

Younossi ZM, Kanwal F, Saab S, Brown KA, El-Serag HB, Kim WR, Ahmed A, Kugelmas M, Gordon SC.

Abstract

BACKGROUND: Infection with the hepatitis C virus (HCV) has been considered a major cause of mortality, morbidity and resource utilisation in the US. In addition, HCV is the main cause of hepatocellular cancer (HCC) in the US. Recent developments in the diagnosis and treatment of HCV, including new recommendations pertaining to screening for HCV by the Centers for Disease Control and Prevention and newer treatment regimens with high efficacy, short duration and the potential for interferon-free therapies, have energised the health care practitioners regarding HCV management.

AIM: To assess the full impact of HCV burden on clinical, economic and patient-reported outcomes.

METHODS: An expert panel was convened to assess the full impact of HCV burden on a number of important outcomes using an evidence-based approach predicated on Grading of Recommendations Assessment, Development and Evaluation methodology. The literature was summarised, graded using an evidence-based approach and presented during the workshop. Workshop presentations were intended to review recent, relevant evidence-based literature and provide graded summary statements pertaining to HCV burden on topics including the relationships between HCV and the development of important outcomes.

RESULTS: The associations of HCV with cirrhosis, HCC, liver-related mortality, type 2 diabetes mellitus, rheumatological diseases and quality of life impairments are supported by strong evidence. Also, there is strong evidence that sustained viral eradication of HCV can improve important outcomes such as mortality and quality of life.

CONCLUSIONS: The current evidence suggests that HCV has been associated with tremendous clinical, economic and quality of life burden.

© 2014 John Wiley & Sons Ltd.

PMID: 24461160 [PubMed - as supplied by publisher]

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Patterns of viral load decline with telaprevir-based therapy in patients with genotype 1 chronic HCV infection

J Clin Virol. 2014 Jan 6. pii: S1386-6532(13)00542-8. doi: 10.1016/j.jcv.2013.12.011. [Epub ahead of print]

Picchio G¹, De Meyer S², Dierynck I², Ghys A², Gritz L³, Kieffer TL³, Bartels DJ³, Witek J⁴, Bengtsson L³, Luo D⁴, Kauffman RS³, Adda N⁵, Sarrazin C⁶.

Abstract

BACKGROUND: Telaprevir-based therapy is associated with rapid decline in HCV RNA, enabling the application of early futility rules.

OBJECTIVES: To familiarize physicians with this paradigm, a comprehensive analysis of the most frequent HCV viral load profiles observed during treatment with telaprevir/Peg-IFN/RBV in Phase III trials is provided.

DESIGN: HCV RNA profiles were analyzed from 320 HCV genotype 1 treatment-naïve patients enrolled in the ADVANCE study, and 225 prior Peg-IFN/RBV treatment-experienced patients enrolled in the REALIZE study. Patients received 12 weeks of telaprevir with either 24 or 48 weeks of Peg-IFN alfa-2a/RBV. Patients with missing SVR assessments during follow-up, detectable HCV RNA at end of treatment but who did not have viral breakthrough (vBT), or with early vBT who discontinued telaprevir before time of failure were excluded.

RESULTS: All analyzed patients experienced a rapid decline in HCV RNA (>2.0 log₁₀) by Day 14, irrespective of baseline characteristics and/or prior response to Peg-IFN/RBV (relapse, partial response and null response). Subsequently, HCV RNA continued to decline to undetectable levels in most patients. These patients went on to have one of the following outcomes: sustained virologic response, late vBT (after Week 12, i.e. during the Peg-IFN/RBV phase), or relapse. In the small subset of patients with early vBT or meeting a futility rule before Week 12, HCV RNA usually never became undetectable and/or increased rapidly after reaching the nadir.

CONCLUSIONS: HCV RNA profiles with telaprevir/Peg-IFN/RBV are different from those with Peg-IFN/RBV alone. It is important that clinicians understand these HCV RNA profiles and monitor patient viral load in order to apply futility rules correctly.

Copyright © 2014. Published by Elsevier B.V.

KEYWORDS: HCV RNA, Hepatitis C, Stopping rule, Telaprevir, Viral load

PMID: 24462470 [PubMed - as supplied by publisher]

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