Why Have Cases of Liver Cancer Tripled?

By: Laurie Stoneham

Published: Jan 4, 2012 02:56 pm

While the prevalence of a number of cancers is declining, some types are on the rise. The incidence of one of the more difficult forms of liver cancer to treat has tripled over the past 30 years. And researchers are beginning to know why.

Hepatitis C infection wreaks havoc on the liver, leaving tissue scarred and permanently damaged. Researchers now believe it's the rise in cases of hepatitis C that's behind the greatest increases in hepatocellular carcinoma (HCC) - liver cancer. Obesity also plays a role in this trend.

study from the Mayo Clinic led by Ray Kim, M.D., a specialist in Gastroenterology and Hepatology, reviewed several decades of data from the Rochester Epidemiology Project. This review uncovered a couple of interesting facts:

• The overall incidence of HCC is higher than what the National Cancer Institute (NCI) estimates - 6.9 cases are found in 100,000 individuals vs. NCI's estimate of 5.1 per 100,000.
• Two decades ago, liver cancer typically resulted from tissue scarring caused by alcohol consumption or cirrhosis.
• HCC is now developing after an individual is infected with the hepatitis C virus.

“The liver scarring from hepatitis C can take 20 to 30 years to develop into cancer,” Dr. Kim says. “We’re now seeing cancer patients in their 50s and 60s who contracted hepatitis C 30 years ago and didn’t even know they were infected,” he said.

Along with liver diseases, 11 percent of HCC cases were associated with obesity, especially fatty liver disease. Dr. Kim believes that due to the nation's burgeoning obesity crisis, rates of liver cancer "may dramatically increase in the foreseeable future.”

“It’s a small percentage of cases overall,” Dr. Kim says. “But with the nationwide obesity epidemic, we believe the rates of liver cancer may dramatically increase in the foreseeable future.”

Another study led by Mayo Clinic researcher Abdirashid Shire, Ph.D, examined Somali immigrants. Hepatitis B, also a risk factor for HCC, is common in that country. Researchers were surprised to learn that even in this population, though, hepatitis C was the primary cause of liver cancer.

Both studies suggest individuals at greatest risk for liver cancer - people who have had hepatitis C and those who were born in countries where hepatitis is more frequent - should be screened for liver cancer, which is most treatable when it's detected early.

These two studies were funded by the National Institutes of Health and the Mayo Clinic Center for Translational Science Activities.

Findings from this research were published in the January issue of Mayo Clinic Proceedings.

Liver Cancer (Hepatocellular Carcinoma

The American Cancer Society estimates that there are over 26,000 new cases of primary liver cancer and bile duct cancer in the United States each year, and they are responsible for over 19,000 deaths. The average man has about a 1% chance of developing this cancer over his lifetime, while the average woman has about a half percent chance.

Primary liver cancer most commonly includes hepatocellular carcinoma (HCC) and can coexist with cholangiocarcinoma, a cancer of the bile ducts between the liver and gall bladder. It is important to note that most cases of cancer in the liver are metastases from other cancers, such as those from the colon, breast, or prostate. Primary liver cancers begin in the liver itself. Other less common forms of primary liver cancer include angiosarcomas and hemangiosarcomas (cancers that begin in the blood vessels of the liver), lymphoma of the liver, and hepatoblastoma (a rare pediatric cancer usually occurring in children under three years of age). There are also several variants of benign liver tumors. Hepatocellular adenomas (a benign liver tumor associated with oral contraceptive use and glycogen storage disease) must be watched closely, as they have a potential to turn cancerous.

Hepatocellular carcinoma, the most common form of liver cancer, is strongly associated with infection by chronic hepatitis B and C. These infections cause liver cancer more often in Asian and African countries where hepatitis viruses are endemic and people acquire the disease early in their life.

Cases of liver cancer in the United States have tripled over the past three decades. While the most common cause of liver cancer used to be from alcohol abuse and the resulting cirrhosis of the liver, hepatitis C infection is now a leading cause. Obesity, particularly fatty liver disease, is also implicated. Other causes include hemochromatosis (a disease that causes the body to store too much iron), high exposure to aflatoxins (a mold found in peanuts, rice, soybeans and corn; rare in developed countries), and Type 2 diabetes.

Symptoms of HCC usually present with classic signs of liver dysfunction such as jaundice (yellowing of the skin due to too much bilirubin), bruising and blood clotting problems (due to the liver making the clotting factors in our blood), and ascites (fluid buildup in the abdomen from liver dysfunction). Other general symptoms include nausea, fatigue, vomiting, and unintentional weight loss.

In patients who are at high risk for HCC, screening is usually done with ultrasound and CT scan, as well as MRI. While there is no reliable blood test for liver cancer screening, a high level of alpha-fetoprotein (AFP) should be considered suspicious for liver cancer. Liver biopsy is also done, although this is not necessary for diagnosis if imaging is definitive.

Treatment for HCC is difficult, as many patients with liver cancer also have damaged livers from cirrhosis. Treatment must be balanced between treating the cancer and also mitigating the risk of liver failure. Early stage cancer has the potential for surgical removal, however most cases of liver cancer are discovered when they are advanced, making surgery difficult. Other treatments are dependent on the size and location of the tumors, such as ethanol injection into the tumor (small tumors), radiofrequency ablation (using high-frequency radiowaves to destroy the tumor), transcatheter arterial chemoembolization (cuts off the blood supply to unresectable tumors), and cryosurgery (destroying cancerous tissue with subzero temperatures). Liver transplantation is a relatively successful option for patients without metastatic spread. Sorafenib (marketed as Nexavar) is a tyrosine kinase inhibitor that has shown efficacy in treating HCC.

Ultimately, HCC is a difficult cancer to treat and survival rates are low, with most cancers being unable to be completely removed. These patients usually succumb to the disease within three to six months. Across the board, patients with a solitary small tumor of less than three centimeters in size have a five-year survival rate of 20%. Patients with advanced disease have a one-year survival rate of 30%.

Prevention of liver cancer is extremely effective if vaccinated against hepatitis B. Avoidance of alcohol abuse is also effective. Other patients with different causes of cirrhosis or chronic liver inflammation will benefit from routine ultrasound screening and AFP measurements in the hope of detecting cancer early.

Reviewed by:

Joseph V. Madia, MD

Review Date:

Wednesday January 4, 2012

Last Updated:

Wednesday January 4, 2012

Citation:

Mayo Clinic, "Mayo Clinic Studies Identify Risk Factors in Rising Trend of Liver Cancer"

1-800-TKO-Cancer

Source 16790.html

Hepatitis C vaccine: Oxford researchers' trial 'promising'

The scientists devised a vaccine which would target the "inner engine" rather than the surface

An early clinical trial of a hepatitis C vaccine has shown "promising" results, according to researchers at Oxford University.

Designing a vaccine has been difficult as the virus changes its appearance, making it hard to find something to target.

Writing in Science Translational Medicine, researchers say their trial on 41 patients shows it is possible.

The Hepatitis C Trust said the findings were very promising.

The virus can go unnoticed for years, but during this time it can cause considerable liver damage.

In the UK, up to 500,000 people may be infected with the virus. The World Health Organization believes the global figure could be as high as 170 million people.

It spreads through blood-to-blood contact such as sharing needles. While infection can be controlled with antiviral drugs, the Oxford University researchers say a vaccine "would be a major step forward".

Shifting target

They attempted to target the inner workings of the virus, rather than the variable surface markings.

While we are hopeful, it could be a long road to any vaccine that protects people against hepatitis C”

End Quote Prof Paul Klenerman Oxford University

One of the researchers, Prof Paul Klenerman, said: "That's where the engine of the virus is, where we may be able to successfully target many of the crucial pieces of machinery."

Cold viruses were modified with genetic material from the hepatitis C virus in order to prime the immune system to attack the hepatitis C virus.

The aim of the Phase I trial was to determine whether the treatment was safe and to help plan future trials.

Forty-one healthy patients were given the vaccine. Scientists said it produced a "very strong" immune response which lasted for at least a year and had no major side-effects.

Prof Klenerman said: "The immune responses we've seen are exciting and we are beginning the next stage of trials. While we are hopeful, it could be a long road to any vaccine that protects people against hepatitis C."

The next step will be to give the vaccine to people at-risk of hepatitis C infection to see whether it protects against the virus.

Charles Gore, chief executive of the Hepatitis C Trust, said: "This is very promising research.

"There has been rapid development in drugs to treat hepatitis C, but vaccine development has lagged behind. Yet, if we only treat existing infections, we will always be behind the curve.

"We badly need to improve prevention and this is an excellent step in that direction."

http://www.bbc.co.uk/news/health-16415225

ACH-1625 Protease Inhibitor Receives Fast Track For The Treatment Of HCV

ACH-1625 Receives Fast Track Designation for the Treatment of Chronic Hepatitis C

NEW HAVEN, Conn., Jan. 4, 2012 (GLOBE NEWSWIRE) -- Achillion Pharmaceuticals, Inc. (Nasdaq:ACHN), a leader in the discovery and development of small molecule drugs to combat the most challenging infectious diseases, announced today the receipt of a Fast Track designation from the U.S. Food and Drug Administration (FDA) for ACH-1625 for the treatment of chronic hepatitis C virus (HCV). ACH-1625 is a once-daily protease inhibitor with broad genotypic coverage against HCV that was discovered by Achillion and is currently being evaluated in a Phase 2 clinical trial.

Fast Track designation was granted to ACH-1625 for its potential to provide:

- Improved safety and tolerability as compared to the current standard of care;

- Convenient once-daily dosing;

- Broader genotypic coverage of HCV;

- An improved drug-drug interaction profile with greater potential to treat HCV patients with comorbidities, co-infected with HIV, or pre- or post-liver transplantation; and

- Development in a once-daily interferon-free oral combination.

"We are very pleased with the granting of a Fast Track designation for ACH-1625, which we believe highlights this protease inhibitor's attributes which include broad genotypic coverage of HCV, once-daily administration and an improved safety, efficacy and tolerability profile over currently approved therapies for HCV," commented Michael Kishbauch, President and Chief Executive Officer of Achillion. "As we work toward achieving our near-term milestones, we remain eager to initiate an interferon-free, all-oral combination clinical study evaluating our protease inhibitor plus NS5A inhibitor for the treatment of HCV during the second half of this year."

Under the FDA Modernization Act of 1997, the Fast Track program facilitates interactions with the FDA before and during the submission of a New Drug Application (NDA) for therapeutics being investigated as a treatment of serious or life-threatening diseases which demonstrate the potential to address an unmet medical need for such a condition. The Fast Track program enables a company to file an NDA on a rolling basis as data becomes available. This permits the FDA to review the filing as it is received, rather than waiting for the entire document prior to commencing the review process. With a Fast Track designation, there is an opportunity for more frequent interactions with the FDA and the possibility of a priority review, which could decrease the typical development time and review period.

About ACH-1625

ACH-1625 is a HCV protease inhibitor designed and synthesized based on crystal structures of enzyme/inhibitor complex. ACH-1625 is an open chain, non-covalent, reversible inhibitor of NS3 protease. In preclinical studies, ACH-1625 demonstrated high potency, unique pharmacokinetic properties and an excellent safety profile at high drug exposures. ACH-1625 has rapid and extensive partitioning to the liver, as well as high liver/plasma ratios. ACH-1625 has shown low single-digit nanomolar potency that is specific to HCV. It is equipotent against HCV genotypes 1a and 1b at IC50 of approximately 1nM.

In the first segment of a Phase 2a clinical study, treatment-naïve genotype 1 HCV patients received doses of 200 mg, 400 mg, or 800 mg of ACH-1625 in combination with pegylated interferon and ribavirin (SOC) and achieved a rapid viral response (RVR) of 75 — 81% compared to an RVR of 20% for patients receiving SOC only. ACH-1625 was well tolerated at all doses with no serious adverse events reported and adverse events which were reported as mild to moderate and transient. The second segment of this Phase 2a, randomized, double-blind trial is evaluating the safety, tolerability and antiviral activity of once daily ACH-1625, at doses of 200 mg, 400 mg or 800 mg, in combination with SOC for 12 weeks of dosing. The primary endpoint for this trial is complete early virological response (cEVR). Following 12 weeks of therapy, patients will continue to receive an additional 12 weeks of pegylated interferon alfa-2a and ribavirin and be eligible to discontinue treatment at week 24 if they achieve extended rapid virologic response (eRVR) at week 12. Patients who do not achieve an eRVR will continue to receive SOC until week 48.

About HCV

The hepatitis C virus infects the liver and is the most common cause of viral hepatitis, which is an inflammation of the liver. It is currently estimated that more than 170 million people are infected with HCV worldwide and The American Association of Liver Disease estimates that up to 80 percent of individuals become chronically infected following exposure to the virus. If left untreated, chronic hepatitis can lead to permanent liver damage, which can result in the development of liver cancer, liver failure or death. Few therapeutic options currently exist for the treatment of HCV infection. The current standard of care is limited by its specificity for certain types of HCV, significant side-effect profile, and an injectable route of administration.

About Achillion Pharmaceuticals

Achillion is an innovative pharmaceutical company dedicated to bringing important new treatments to patients with infectious disease. Achillion's proven discovery and development teams have advanced multiple product candidates with novel mechanisms of action. Achillion is focused on solutions for the most challenging problems in infectious disease including hepatitis C and resistant bacterial infections. For more information on Achillion Pharmaceuticals, please visit www.achillion.com or call 1-203-624-7000.

Forward-Looking Statements

This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other important factors that could cause actual results to differ materially from those indicated by such forward-looking statements, including statements with respect to the potency, safety and tolerability over currently-approved therapies, increased effectiveness and other characteristics of ACH-1625, Achillion's expectations regarding timing for the commencement, completion and reporting of results from clinical trials of Achillion's protease inhibitors, and the potential benefits of Fast Track designation for ACH-1625. Among the important factors that could cause actual results to differ materially from those indicated by such forward-looking statements are risks relating to, among other things: Achillion's ability to: replicate in later clinical trials positive results found in earlier stage clinical trials of ACH-1625 and its other product candidates; advance the development of its drug candidates under the timelines it anticipates in current and future clinical trials; obtain necessary regulatory approvals; obtain patent protection for its drug candidates, and the freedom to operate under third party intellectual property; establish commercial manufacturing arrangements and to identify, enter into and maintain collaboration agreements with appropriate third-parties; compete successfully with other companies that are seeking to develop improved therapies for the treatment of HCV; and raise the substantial additional capital needed to achieve its business objectives. These and other risks are described in the reports filed by Achillion with the U.S. Securities and Exchange Commission, including its Annual Report on Form 10-K for the fiscal year ended December 31, 2010 and its subsequent SEC filings.

In addition, any forward-looking statement in this press release represents Achillion's views only as of the date of this press release and should not be relied upon as representing its views as of any subsequent date. Achillion disclaims any obligation to update any forward-looking statement, except as required by applicable law.

CONTACT: Company Contact:

Glenn Schulman

Achillion Pharmaceuticals, Inc.

Tel. (203) 752-5510

gschulman@achillion.com



Investors:

Mary Kay Fenton

Achillion Pharmaceuticals, Inc.

Tel. (203) 624-7000

mfenton@achillion.com



Media:

Christin Culotta Miller

Ogilvy PR

Tel. (212) 880-5264

christin.miller@ogilvy.com

Hepatitis C and Liver Health-Getting It Right In 2012

Its a new year, right?

Yep, its 2012, a time for shaping up, eating right and addressing all those unhealthy habits from 2011. Enter - liver disease, hepatitis C, and a few healthy ways to improve liver health.

Note To Self ?

1-I promise to spend only 8 hours on the computer-Not 12.
2-I promise to only smoke when I tweet- Abstain on facebook.
3-I promise to watch less TV- Only stream Netflix to my computer.
4-I promise to stop eating fast food-Only eat from the dollar menu.
5- I promise to give up alcohol-Only drink on weekends.
6-I promise to detox my liver in January-Can't wait for February.

I sure hope this doesn't sound like you. If you're one of the millions of people who start off January in liver rehab, but end up in February with a liver relapse, consider a life long commit to your liver.

Is it time to detox your liver?

Recently, the British Liver Trust launched a national awareness campaign for the month of January, with an emphasis on the increased risk of liver disease from alcohol use. The campaign also advises that eating well and regular exercise should be an ongoing effort.

Some advice on that "January liver detox" from Andrew Langford, the chief executive from the British Liver Trust.

“While people believe the hype and go on January detoxes to 'rejuvenate' their liver, it would actually be more beneficial to adopt a more long-term attitude to achieving good liver health. People think they're virtuous with their health by embarking on a liver detox each January with the belief that they are cleansing their liver of excess following the festive break. A one-hit, one-month attempt to achieve liver health is not the way to approach it. You're better off making a resolution to take a few days off alcohol a week throughout the entire year than remaining abstinent for January only.”

Hepatitis C and Alcohol

However, its a different story if you're living with hepatitis C. Taking a few days off from drinking alcohol a week isn't in the plan.

If you have HCV - Drinking alcohol is associated with a 30 times increased risk of cirrhosis.

If you have HCV - Drinking alcohol during HCV therapy will interfere with antiviral effectiveness and treatment adherence.

If you have HCV - Studies have shown that alcohol abuse increases your chance for death, compared to those who have hepatitis C and do not drink.

If you have HCV - and alcoholic liver disease, the chance of developing HCC is higher than if you have hepatitis C alone.


First Tip For Improving Liver Health In 2012

According to The Hepatitis Foundation International

You'll need to stop drinking completely to give your liver a break - a chance to heal, a chance to rebuild, a chance for new liver cells to grow. This means avoiding beer, wine, cocktails, champagne, and liquor in any other form. If you continue to drink, your liver will pay the price, and if your doctor is checking your liver function tests, it may be hard to determine if a change in a test means there has been damage to your liver due to the disease itself or because of the alcohol.

Vitamins

What about using antioxidant supplements such as; (beta-carotene, vitamin A, vitamin C, vitamin E, or selenium) for improving liver health?

Excessive amounts of some vitamins may be an additional source of stress to the liver that must act as a filter for the body. Mega-vitamin supplements, particularly if they contain vitamins A and D, may be harmful. Excess vitamin A is very toxic to the liver.

Reported in The Cochrane Database of Systematic Reviews 2011 Issue 3 , no beneficial evidence was found for using antioxidant supplements for the treatment of liver diseases.

Beta-carotene, vitamin A, vitamin C, and vitamin E cannot be recommended for treatment of liver diseases.

An imbalance between too much oxidative stress and too little antioxidative defence has been suggested to cause a variety of liver diseases. Therefore, antioxidant supplements (beta-carotene, vitamin A, vitamin C, vitamin E, and selenium) could have a potential role in patients with liver disease. The evidence on whether antioxidant supplements are effective in treatment of liver diseases is contradictory.

In this review treatment with antioxidant supplements of alcoholic, autoimmune, hepatitis B or hepatitis C virus liver diseases, or liver cirrhosis is assessed.

The review includes 20 randomised clinical trials. In total, 1225 participants were randomised to antioxidant supplements (beta-carotene, vitamin A, vitamin C, vitamin E, and selenium) versus placebo or no intervention. The low number of randomised participants increases the risk of random errors ('play of chance'). Trial quality was low and accordingly the risk of systematic errors ('bias') was high.

Based on the conducted randomised clinical trials, convincing evidence that beta-carotene, vitamin A, vitamin C, and vitamin E or their combinations are beneficial for treatment of alcoholic, autoimmune, hepatitis B or hepatitis C virus liver diseases, or liver cirrhosis could not be found.

View the abstract here.

What about vitamin D ?

In the January 2012 hepatitis C newsletter from HCV Advocate a study on vitamin D3 supplementation was highlighted, more below, click here to view the abstract.

Article

Vitamin D: An Innate Antiviral Agent Suppressing Hepatitis C Virus in Human Hepatocyte –
Gal-Tanamy M, Bachmetov L, Ravid A, Koren R, Erman A, Tur-Kaspa1R, Zemel R. Source: Hepatology; Volume 54, Issue 5, pages 1570–1579, November 2011.

This study looked at the connection between vitamin D3 supplementation and improved response rates to treatment for chronic hepatitis C virus (HCV) infection. The research showed the various pathways that vitamin D3 uses, showing the antiviral properties of vitamin D3 particularly during interferon treatment. Researchers noted that vitamin D3 combined with interferon alfa has a synergistic relationship (the drug interactions are magnified, in this case in a beneficial way).

Also noted was that vitamin D3 combined with interferon alfa decreases viral production more than interferon alfa without vitamin D3.

The Bottom Line: Vitamin D3 may have a significant impact on HCV and treatment for it.

Should People With Hepatitis Be Tested for Vitamin D ?

Presented at last years DDW, researchers reported that low levels of vitamin D were found in 64% of patients with chronic hepatitis B or hepatitis C. The study was was based on 2,312 viral hepatitis patients treated at Weill Cornell Medical Center between 2007 and 2009.

Among these patients, 395 of 2,312 had been tested for vitamin D levels. In those tested, 122 of 395 were vitamin D insufficient and 132 of 395 were vitamin D deficient.

View the complete article written by David Wild here or here.

Institute of Medicine Weighs In On Vitamin D

In 2010 the Institute of Medicine (IOM ) released new guidelines for vitamin D.

Published at Medpage

Because the IOM could not find evidence to support extraskeletal benefit for vitamin D or calcium, the authors of the report decided to base daily intake recommendations on the amount needed for the maintenance of bone health.

For calcium, they reported that children ages 1 to 3 need about 500 mg each day, and those between 4 and 8 have an average requirement of 800 mg a day. The requirement rises to 1,300 mg a day for adolescents, who experience growth spurts and enhanced bone growth, and falls back to 800 mg each day for adults up to the age of 70.

Women between 50 and 70 are exceptions; they should be receiving 1,000 mg of calcium a day, as should all adults 71 and older.

Dietary Reference Intakes For Calcium and Vitamin D

Click On Image To Enlarge

Hepatitis C; Vitamins And Liver Disease

. Fat soluble vitamins (especially vitamins A, D, and E) can accumulate in the liver, and if taken in "megadose" quantities may damage even normal livers. Vitamin A is perhaps the most toxic of this group with accidental overdosages causing fulminant liver failure. For this reason, no more than standard recommended daily allowances (RDA's) of vitamins A, D and E are suggested for those with liver disease, regardless of the cause. Vitamin K is also a fat soluble vitamin, supplements of Vitamin K generally are not taken, nor are they recommended.

.

Be careful with dietary supplements..

Iron and Vitamin C

Some people with hepatitis C, particularly those with cirrhosis, have above-average levels of iron in their body. Too much iron can damage organs.

If these people take multivitamin/mineral pills, they should take the ones without iron. These pills usually are marketed as formulas for men or adults over 50. These people also should avoid taking large doses of vitamin C because vitamin C helps the body absorb iron.

.
Vitamin A

Vitamin A, if taken in doses larger than the recommended 10,000 IU, can harm the liver. Vitamin A is even more toxic in someone who drinks alcohol.
You won't get too much vitamin A from food, but be careful taking routine dietary supplements with high doses. There's a non-toxic form of vitamin A, present in many fruits and vegetables, called beta-carotene. If you take vitamin A supplements, look for those with beta-carotene.

.

Vitamin E

Researchers are looking into ways that vitamin E can reduce risk of many diseases. But, current medical opinion is that the amount of vitamin E in a well-balanced diet is the safest amount to take.

.
Avoid supplements with doses greater than 400 IU. At high doses, vitamin E can thin the blood. This can be a problem for some people, so never take high-dose supplements without first talking to your doctor.

.
Vitamin K

Vitamin K is involved in blood clotting. It is present in the diet mostly in green vegetables. It also is produced by bacteria in the intestines. As mentioned above Vitamin K supplements are not generally used, or recommended.


Second Tip For Improving Liver Health In 2012

Visit -The Blog of Dr. Joseph S. Galati

Over at the physicians blog is an ongoing nutrition plan to start the new year.

Every day we are launching the January 2012 collection of daily blog entries for the “31 Days of Wellness”, our annual celebration of the New Year, and the opportunity to start anew as we ring in the New Year.

Click here to visit


Visit - The Web Site of Dr. Andrew Weil

Getting healthy need not be overwhelming. Here are six simple, straightforward ways to get on track toward optimum health in 2012.

The anti-inflammatory diet can help you correct that: it points the way to food choices that can help you remain optimally healthy. Here's a link to the anti-inflammatory food pyramid. Print it out and post it on the fridge. Along with influencing inflammation, the diet will give you steady energy and provide all the vitamins, minerals, essential fatty acids and dietary fiber you need.

Click here to visit

Third Tip For Improving Liver Health In 2012

For people living with liver disease caution is advised when taking prescription drugs and over the counter (OTC) drugs.

Acetaminophen is an active ingredient in more than 200 other medications, including Nyquil and Anacin 3 as well as most over the counter standard pain killers. Despite the painkiller alternatives for hepatitus (HCV), it is advisable to speak with your doctor before trying anything to confirm that the painkiller is safe for you to use as most drugs may place additional liver strain on anyone living with Hepatitis C.

Ibuprofen – (Motrin, Advil, Nuprin and others) reduces high body temperature, is an anti-inflammatory and inhibits normal platelet function. A non-steroidal anti-inflammatory drug (NSAID), ibuprofen can cause gastrointestinal upset and bleeding. Those at risk of portal hypertension are already at risk for gastrointestinal bleeding, intensifying this risk. Studies have demonstrated that at certain dosages, ibuprofen can stress the liver and elevate liver enzymes in people with Hepatitis C. Ibuprofen must be used with extreme caution in the later stages of liver disease and for those on interferon therapy.

Aspirin – (Bayer, Anacin, Excedrin and others) reduces fever, relieves pain, and acts as an anti-inflammatory and blood thinner. In addition to influencing liver test results, aspirin’s effect on blood platelets temporarily limits the clotting process and prolongs bleeding. In chronic liver disease where the body’s production of clotting factors is naturally decreased, aspirin can increase the risk of bleeding. Although there is no actual drug interaction between aspirin and the drugs used in interferon therapy, both can disrupt blood clotting, which must be monitored if used together. When taken in high doses (more than 2,000 mg per day) aspirin can cause liver injury.

Source


Medications for sleep in liver disease

Excerpt taken from an article written in 2011 by Jennifer Pate

Read the full article here.

Sleep medications are problematic in the context of liver disease and require careful monitoring and weighing of the risks and benefits. I have mentioned a few of the more commonly used medications for sleep, but this list is not all-inclusive.

Ambien (Zolpidem) is a commonly used medication that may help people who have difficulty falling asleep. Ambien may worsen encephalopathy in cirrhosis. Ambien has also been noted to worsen memory problems in patients on Interferon.

Hydroxyzine is an antihistamine that was recently studied in a group of patients with cirrhosis. In very low doses, this may be a safe drug to use to treat insomnia on a short term basis. However, all antihistamines have the potential to worsen confusion. Benadryl (Diphenhydramine) is also an antihistamine which is sometimes used for insomnia. Patients quickly develop a tolerance to the sedative effect and may also experience side effects such as worsening confusion, dry mouth, urinary retention or constipation.

Lunesta (Eszopiclone) is a sleep medication with low abuse potential. An additional benefit is that tolerance does not appear to develop. Studies of this medication in patients with liver disease have not been conducted, but preliminary information suggests this may be a safer option for the treatment of insomnia.

Trazodone is an antidepressant medication that is used primarily for sleep. It may be effective for patients who experience trouble falling asleep as well as staying asleep. It has a rare risk of priapism (an abnormal erection that will not resolve). In some studies, Trazodone has caused reversible abnormalities in liver function tests. Trazodone may cause dizziness or residual sedation during the day.

Benzodiazepine medications such as Xanax (Alprazolam), Restoril (Temazepam), or Klonopin (Clonazepam) may interfere with the amount of time spent in each stage of sleep (sleep architecture). Xanax is highly addictive and is not safe in liver disease. Benzodiazepines such as Restoril or Klonopin are safer in liver disease, but may worsen encephalopathy. Benzodiazepines and alcohol are a deadly combination and can cause respiratory depression. If benzodiazepines are abruptly stopped after long term use, a potentially life threatening withdrawal syndrome may result.

Drug Interactions Treating With Boceprevir or Telaprevir

If you are treating HCV with one of the new FDA apporved protease inhibitors, know that other drugs you might be taking can cause serious drug interactions.

The list of drugs can be found at Medscape, along with a drug interaction checker.

Boceprevir - Telaprevir

*Free registration is required


Third Tip For Improving Liver Health In 2012

Diet and Your Liver

Overview
Poor nutrition is rarely a cause of liver disease, but good nutrition in the form of a balanced diet, may help liver cells damaged by hepatitis viruses to regenerate, forming new liver cells. Nutrition can be an essential part of treatment. Many chronic liver diseases are associated with malnutrition.

Watch the Protein
To quickly determine your daily protein in grams, divide your weight in pounds by 2. Too much daily protein may cause hepatic encephalopathy (mental confusion). This occurs when the amount of dietary protein is greater than the liver's ability to use the protein. This causes a build up of toxins that can interfere with brain function. Protein is restricted in patients with clinical evidence of encephalopathy. However, controversy exists regarding the type of protein a diet should contain. Vegetable and dairy protein may be tolerated better than meat protein. Medications, such as lactulose and neomycin, may be used to help control hepatitis-related encephalopathy. Due to the body's need for proteins, protein restriction should only be undertaken with a doctor's advice.

Watch the Calories.
Excess calories in the form of carbohydrates can add to liver dysfunction and can cause fat deposits in the liver. No more than 30% of a person's total calories should come from fat because of the danger to the cardiovascular system. To figure out your daily calorie needs, you'll need a minimum of 15 calories a day for each pound you weight.

Watch the Salt
Good nutrition also helps to maintain the normal fluid and electrolyte balances in the body. Patients with fluid retention and swelling of the abdomen (ascites), or the legs (peripheral edema), may need diets low in salt to avoid sodium retention that contributes to fluid retention. Avoiding foods such as canned soups and vegetables, cold cuts, dairy products, and condiments such as mayonnaise and ketchup can reduce sodium intake. Read food labels carefully as many prepared foods contain large amounts of salt. The best-tasting salt substitute is lemon juice.
Source


Final Tip

Learn as much as you can about hepatitis C, begin by reading the December 2011 updated fact sheet from HCV Advocate

Living with Hepatitis C:
Managing Common Symptoms

Lucinda K. Porter, R.N.
Alan Franciscus

Click here to view the upate

The Bottom Line

The best way to receive all the important vitamins and nutrients needed to insure a healthy liver is by eating a balanced diet. To learn more about a healthy diet for people living with liver disease click here.

Results:CF102 in the treatment of hepatocellular carcinoma (HCC).

Can-Fite BioPharma Announces Successful Results of its Phase I/II Liver Cancer Study with its CF102 Drug; the Study Achieved the Primary and Secondary Endpoints

Can-Fite BioPharma Ltd (TASE:CFBI), a biotechnology company developing small molecule drugs for the treatment of inflammatory, and liver diseases, traded on the Tel Aviv Stock Exchange announced today the successful results of the Phase 1/2 study of its drug candidate CF102 in the treatment of hepatocellular carcinoma (HCC).

The company also announced today that a separate phase 1/2 study in patients with Hepatitis C (HCV) reached the study's main objectives of safety and pharmacokinetic behavior.
The HCC study which was conducted under the supervision of Dr. Salomon M. Stemmer, Institute of Oncology, Davidoff Center, Rabin Medical Center, included 18 patients with HCC, most of them had failed prior treatment with Sorafenib (Nexavar), the only currently approved drug for this indication.

The primary study objectives were to evaluate the safety profile of long-term administration of CF102 at 3 different dose levels in patients with HCC, and to determine the pharmacokinetic behavior of CF102 in this patient population. The secondary objective of the trial was to document evidence of clinical efficacy and to look at the correlation between A3 adenosine receptor expression levels at base line and patients' response to CF102.

The study data demonstrate that the trial objectives were successfully achieved, showing a very favorable safety profile for CF102 in a patient population with hepatocellular carcinoma and Child-Pugh cirrhosis classes A and B. In addition, the median overall survival time was 7.8 months, which is very encouraging data given that most patients were treated in the second-line setting and some were Child-Pugh class B. Remarkably, the median overall survival time of the Child-Pugh B patients was 9.4 months, the longest overall survival time that has been reported in the literature for this patient population.

Out of the 18 patients, 9 were infected with Hepatitis C. In 7 patients treated with the high CF102 dosages, a reduction in HCV load was observed.

According to Dr. Keith Stuart, MD, Chairman, Department of Hematology and Oncology, Lahey Clinic Medical Center, Professor of Medicine, Tufts University School of Medicine: "The safety and efficacy data of the CF102 Liver Cancer study are impressive and encouraging in the context of other investigational drugs. Therefore, I would recommend further clinical development of this drug for the treatment of patients with hepatocellular carcinoma. I hope that the present data will be reproducible and that patients could benefit from this drug."
In parallel, the company also announced today that a separate phase 1/2 study in patients with Hepatitis C (HCV) reached the study's primary objectives of safety and pharmacokinetic behavior. However, a reduction in the HCV viral load was not observed. It should be noted that patients on this study were treated for several months only with the low dose of CF102.
According to Dr. Pnina Fishman, the company CEO, "We are very pleased that the study achieved all of its objectives in patients with HCC, most of whom had failed prior treatment with Nexavar. The impressive results in the HCC study encourage us to continue development of CF102 in patients with Liver Cancer. We will focus on this disease and will continue to observe the viral load of HCC patients who also suffer from HCV."

CF102 is a small orally bioavailable drug which binds with high affinity and selectivity to the A3 adenosine receptor. The latter is highly expressed in tumor cells whereas low expression is found in normal cells. This differential effect accounts for the excellent safety profile of the drug. The drug induces a robust anti-tumor effect via de-regulation of the Wnt signaling pathway, resulting in apoptosis of liver cancer cells agonist at the A3 adenosine receptor.
About Can-Fite Biopharma Ltd.

Can-Fite Biopharma Ltd is a public company, trading on the Tel Aviv Stock Exchange. The company, which commenced business activity on 2000, was founded by Prof Pnina Fishman, researcher in the Rabin Medical Center, and Dr Ilan Cohen, patent attorney and senior partner at Reinhold Cohen Patent Attorneys. Prof Fishman serves as CEO of the company. The company was founded on the basis of Prof Fishman's scientific findings, and is focused on the development of small molecule drugs, ligands to the A3 adenosine receptor. The latter mediates anti-inflammatory and anti-cancer effects and is suggested as a biological predictive marker. The company's lead drug, CF101, is in advanced clinical development for the treatment of autoimmune inflammatory diseases. The CF102 drug candidate is being developed for the treatment of liver diseases. Can-Fite has a wealth of clinical experience: to date, more than 700 patients have participated in clinical trials conducted by the company. Can-Fite recently licensed its activity in the ophthalmic field to OphthaliX Inc.

About OphthaliX Inc (formerly Denali Concrete Management Inc).
OphthaliX Inc. (OTCBB:DCMG) is an advanced clinical-stage biopharmaceutical company focused on developing therapeutic products for the treatment of ophthalmic disorders. Denali's product candidate, CF101, is being developed to treat three ophthalmic indications: dry eye syndrome; glaucoma and uveitis. Can-Fite holds 82.3% in OphthaliX Inc.
Can-Fite BioPharmaPnina Fishman, Ph.D., Chief Executive OfficerTel: +972-3-9241114Fax: +972-3-9249378

pnina@canfite.co.ilhttp://cts.businesswire.com/ct/CT?id=smartlink&url=http%3A%2F%2Fwww.canfite.com%2F&esheet=50118903&lan=en-US&anchor=http%3A%2F%2Fwww.canfite.com&index=1&md5=af5a23fca4c73f2d3252e21ea76b556e
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Mayo study links hepatitis C to liver cancer

Mayo study links hepatitis C to liver cancer
by Rupa Shenoy, Minnesota Public Radio
January 3, 2012

St. Paul, Minn. — The Mayo Clinic released a study today that identifies hepatitis C as a cause of rising liver cancer rates. Researchers say with that information, more people can be screened for hepatitis C and prevent cancer.

The finding may have a particular impact on the Somali community. That's because a second study published by Mayo today says hepatitis C rates among Somalis are much higher than previously suspected.

The first study from the Mayo Clinic confirms that scarring from hepatitis C can develop over decades into liver cancer. The study used a database of medical records for everyone who's had inpatient or outpatient care in Olmsted County. The database includes comprehensive information about each patient, making it possible for researchers to find patterns that weren't apparent before.

The study, while in progress, caught the attention of Mayo researcher Abdirashid Shire, who visits most of the Somali patients at Mayo and is Somali himself. He's seen many friends die of advanced liver cancer. So Shire led a second study by digging into the Mayo database, picking out the Somali names, and looking for patterns.

"When we looked at those who develop liver cancer, during the timeframe we looked at between 1996 and 2001, we found 30 people who developed liver cancer," said Shire. "And can you imagine -- almost 80 percent, the liver cancer was due to hepatitis C."
Until now, Shire says the medical community only knew of one strain of the hepatitis virus prevalent among sub-Saharan Africans -- hepatitis B. Currently, Somali refugees coming to the US aren't even regularly screened for hepatitis C. Shire says if they were, doctors could catch liver problems before they progress past the point of treatment.

There are few early signs of hepatitis C. The virus is transferred through sex or blood transfusions -- and it can run rampant in places like Somalia or African refugee camps, where physicians may not always sterilize needles thoroughly between patients.
Shire says people often don't know they have hepatitis C until decades after the initial infection. By that time, it can be too late.

Amina Arele, 66, sits in a hospital room with tubes running from her nose and IVs taped to her left forearm. Arele got a liver transplant three days earlier. She was diagnosed with liver cancer this summer, although she had always been healthy to that point. Arele likely would have died without the liver transplant, since only about one in 10 people diagnosed with advanced liver cancer survives.

Arele says her husband had hepatitis C when they lived in Somalia 30 years ago. She is not sure when she contracted the disease from him, but believes it was just recently.
Arele's son, Rashad Hassan, says this has been a wakeup call for his family.
"One of the things that ... the family members decided to do is make sure we have hepatitis C testing," said Hassan.

Arele's transplant doctor, Mohammad Hassan, says that family approach is important.
"There's a lot of extended family decisions involved here," said Hassan. "You have to talk with the cousin, you have to talk with the uncle, you have to talk with the wife, you have to talk with the children, if they are old enough."
Hassan says Somalis tend to make decisions as a community, so education on this issue is a big job.

Hassan and researcher Abdirashid Shire are just starting that effort, by speaking to community groups and on Somali TV. They know there's no time to lose -- Shire lost a good friend to liver cancer just a few weeks ago.

Abdullahi Abdi Hassan was a small businesses owner in Eden Prairie. His sister, Ayan Hassan, says he brought 24 family members to this country and paid to educate each one. Ayan Hassan, who's a nurse, says her brother got hepatitis C through a blood transfusion in Somalia.
"It really upset me when I find out his doctor was not doing ultrasound, because people who have hepatitis should get blood drawn every year and they should be getting ultrasound every six months," she said.

Abdullahi Hassan was diagnosed with liver cancer this fall. Surgery didn't help. He was in the hospital for three weeks before he died.

Ayan Hassan says dozens of Somalis came to see her brother every day, and he told all of them to make an appointment to get tested with his friend, Mayo researcher Abdirashid Shire.

http://minnesota.publicradio.org/display/web/2012/01/03/liver-cancer-somalis-hepatitis/

HCV News Ticker: American scientist arrested in stem-cell clinic sting

Video

Hepatitis C Infection: Recent Advances in Treatment

Dr. Sanjeeva T Reddy Speaks about Hepatitis C Infection and Recent Advances in Treatment in International CME, held on December 29, 2011, at 2PM at Taj Deccan Hotel, Hyderabad



Hepatitis C Infection: Recent Advances... by teluguone


HCV Screen Based on Birth Cohort Proves Cost-Effective
By Kristina Fiore, Staff Writer, MedPage Today
Published: January 02, 2012
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco.

Screening patients for hepatitis C virus (HCV) based on their age rather than their risk is cost-effective, this study suggests.

Note that HCV birth-cohort screening appears to rank on par with colorectal cancer screening, hypertension screening, influenza vaccination of adults ages 50 and up, and vision screening and pneumococcal vaccination of patients ages 65 and up.

Screening patients for hepatitis C virus (HCV) based on their age rather than their risk was cost-effective, researchers found.Birth-cohort screening would cost between $15,700 and $35,700 per quality of life year (QALY) saved depending on the treatment strategy, putting it in a cost-effectiveness range with other widely implemented preventive interventions, David Rein, PhD, of the University of Chicago, and colleagues reported in the Annals of Internal Medicine.

"[It] appears to be a reasonable strategy to identify asymptomatic cases of HCV," they wrote.

The CDC currently recommends screening patients who may be at risk of HCV, such as injection-drug users or those with elevated alanine aminotransferase levels.

But no more than 50% of patients who are chronically infected with the virus are aware of their status. That may be a result of difficulty implementing risk-based screening methods or the awkwardness of discussing behavioral risks, the researchers said.

Expanding screening recommendations to cover patients born between 1945 and 1965 -- those in whom prevalence of HCV is highest -- may be a complement or alternative to risk-based screening, they wrote, although its impact on healthcare costs has been unknown.

So to estimate the cost-effectiveness of birth cohort screening, Rein and colleagues used data from the National Health and Nutrition Examination Survey (NHANES) 2001-2006 on patients who had at least one or more annual visits to a primary care doctor.

They found that, compared with current practices, birth cohort screening identified an estimated 808,580 additional cases of chronic HCV infection at a cost of $2,874 per case identified.

If birth cohort screening was followed by standard treatment with pegylated interferon and ribavirin, screening increased QALYs by 348,800 and costs by $5.5 billion, for an incremental cost-effectiveness ratio (ICER) of $15,700 per QALY gained.

They added that treatment would prevent 82,300 deaths.

If screening were followed by standard-of-care pegylated interferon plus ribavirin in addition to a direct-acting antiviral, a newer class of HCV drugs, QALYs would be increased by 532,200 and costs by $19 billion, amounting to an ICER of $35,700 per QALY saved.

This treatment strategy would prevent 121,000 deaths, the researchers estimated.

They wrote that although there's no accepted standard for determining what level of cost-effectiveness justifies implementing of a new screening strategy, HCV birth-cohort screening appears to rank on par with colorectal cancer screening, hypertension screening, influenza vaccination of adults ages 50 and up, and vision screening and pneumococcal vaccination of patients ages 65 and up.

They warned that the study had several limitations, including relying on the assumption that patients without insurance weren't offered treatment. Also, cost-effectiveness estimates of direct-acting antivirals plus standard treatment were speculative because actual data on their clinical implementation haven't yet been reported.

They also cautioned that disease progress was capped at 20 years, which may be an underestimate, and the study may lack generalizability because NHANES data don't include information on institutionalized or homeless patients, who may be at risk of HCV.

New year, new Florida laws in effect
January 02, 2012 9:24 PM

Hepatitis C virus hijacks liver microRNA

Mechanism explains how virus survives in the liver and how a new antiviral works

Chapel Hill, NC – Viral diseases are still one of the biggest challenges to medical science. Thanks to thousands of years of co-evolution with humans, their ability to harness the biology of their human hosts to survive and thrive makes them very difficult to target with medical treatment.

Scientists at the University of North Carolina at Chapel Hill, working with colleagues from the University of Colorado, have shown for the first time how a small RNA molecule that regulates gene expression in human liver cells has been hijacked by the hepatitis C virus to ensure its own survival – helping medical scientists understand why a new antiviral drug appears to be effective against the virus.

MicroRNAs are involved in regulating the expression of genes in cells, usually by blocking the production of key proteins or by destabilizing the messenger RNAs that encode the cell's proteins as it grows and divides. Normally they act by downregulating gene expression. The research team found that the binding of a prominent microRNA in liver cells, called miR-122, to the viral RNA results in its stabilization, promoting efficient replication of the virus genome in the liver and supporting the virus' lifecycle.

"The hepatitis C virus has done two very interesting things with miR-122," says Stanley M. Lemon, MD, professor of medicine and microbiology and immunology and a member of UNC Lineberger Comprehensive Cancer Center and the Center for Translational Immunology.

"First, it has evolved a unique relationship with a key regulator, since miR-122 represents about half of all microRNAs present in the liver. Second, the virus has usurped a process that usually downregulates gene expression to upregulate the stability of its RNA and expression of viral proteins needed for its lifecycle. It's a classic example of how viruses subvert normally beneficial functions of the cell to their own nefarious purposes."

Work by Dr. Lemon and his colleagues in 2005 helped to demonstrate that miR-122 was required for hepatitis C to replicate itself, but the mechanism was not understood. Now the UNC research team has shown how it works, which helps to explain how a new experimental antiviral drug target the virus. The drug, called an "antagomer", binds to miR-122 and sequesters it in the liver and thus destabilizes the viral genome, accelerating its degradation in the liver. Results of the most recent study are published online this week in the journal Proceedings of the National Academy of Sciences.

Hepatitis C is a continuing public health problem, which is difficult to measure because symptoms occur months to years after infection. The Centers for Disease Control and Prevention estimates as many as 4 million people in the United States may be persistently infected with hepatitis C virus, and most do not know they are infected. More than a third of those who are long-term carriers may develop chronic liver disease or liver cancer, a deadly form of cancer that is becoming increasingly common due to the spread of this virus.

Other members of the research team include Tetsuro Shimakami, Daisuke Yamane, Rohit Jangra and Carolyn Spaniel from UNC Lineberger Comprehensive Cancer Center and the division of infectious diseases at UNC-Chapel Hill School of Medicine and Brian J. Kempf and David Barton from the department of microbiology at the University of Colorado School of Medicine.

The research was funded in part by UNC Lineberger's University Cancer Research Fund and the National Institutes of Health as well as a Gastrointestinal Special Program of Research Excellence (SPORE) Grant at the University of Kentucky Markey Cancer Center.

Podcast

TWiV 164: Six steps forward, four steps back
Podcast-Vincent, Alan, and Rich review ten compelling virology stories of 2011.

Ten virology stories of 2011:

1. XMRV, CFS, and prostate cancer
   
2. Influenza H5N1, ferrets, and the NSABB
   
3. The Panic Virus
   
4. Polio eradication
   
5. Viral oncotherapy
   
6. Hepatitis C virus
7. Zinc finger nuclease and HIV therapy
   
8. Bacteria help viruses
   
9. Human papillomaviruses
   
10. Combating dengue with Wolbachia
    

Click Here To Listen To Podcast

Hall Of Shame

American scientist arrested in stem-cell clinic sting

Posted by Roxanne Khamsi Categories: Stem cells/cloning

Cross-posted from the Nature News Blog

An American university scientist was arrested on 27 December, accused of supplying stem cells for use in unapproved therapies.

The US Department of Justice says Vincent Dammai, a researcher at the Medical University of South Carolina (MUSC) in Charleston, supplied the stem cells without the approval of his university or of the US Food and Drug Administration. Two other men, Francisco Morales of Brownsville, Texas, and Alberto Ramon, of Del Rio, Texas, were also arrested this week as part of the case. A fourth man, Lawrence Stowe of Dallas, Texas, has been charged and a warrant is out for his arrest, according to an FBI press release.

Click here to continue reading.

Off The Cuff

Most Shocking Moments in Celebrity Health

2011 Year in Review: 27 Most Shocking Moments in Celebrity Health
By: Michele R. Berman, MD

Listed below are our Top 27 Teachable Moments* in celebrity health, selected from 300 stories published this year.

Charlie Sheen Will Make Your Face Melt Off
Michael Douglas Beats Throat Cancer
Bret Michaels Survives Heart Surgery
Barbara Walters Opens Her Heart to the World
Serena Williams Undergoes Treatment for Pulmonary Embolism
Matthew Morrison’s Sweet Potato Abs
Keenan Cahill is Dynamite!
Missy Elliot with Graves
Harry Potter was an Alcoholic?!
R. Kelly Has a Bump N’ Grind Removed (from his throat)
Angelina Jolie Eats Bugs
Kim Kardashian Gets a Nasty Rash
I’ll take “Kick Ass Game Show Hosts For $100, Alex”
Dianna Agron Gets a Broken Nose
Sean Kingston looks at Beautiful Girls, Crashes Jet Ski & Nearly Dies, Twice!
Steven Tyler Slips in the Tub
Tanorexics Everywhere! [Snookie, George Hamilton, Rebecca Minkoff]
Bono’s Heart Skips a Beat
Venus Williams Leaves US Open
Don’t Chew Anything Around Kelly Ripa
John Mayer Silenced
Demi Lovato Does What Few Actresses Do
Wanda Sykes says Breast Cancer is No Laughing Matter
Did Alternative Medicine Kill Steve Jobs?
Adele Can’t Sing
Gabby Giffords learns to speak again
They’re letting Khloe Kardashian Have a Baby?!

Continue Reading At Celebrity Diagnosis

Hepatitis C (DAA) drugs - The invaders and the barrier

Journal of Hepatology
Volume 56, Issue 1 , Pages 11-13, January 2012

Jean-Michel Pawlotsky⇑
National Reference Center for Viral Hepatitis B, C and Delta, Department of Virology, Hôpital Henri Mondor, Université Paris-Est,
51 avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France; INSERM U955, Créteil, France

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The invaders and the barrier

Barriers exist to protect. The first images of World War II show the invaders breaking a barrier at the border of Poland, signifying the end of a peaceful world and the beginning of chaos… This is analogous to viral resistance to antiviral drugs. The invader is the drug-resistant virus; this virus preexists as poorly fit, minority viral populations. The “barrier to resistance” of a drug or a drug combination prevents their outgrowth in the presence of the drug(s), thus preventing virological breakthrough, disease progression, and eventually severe complications. If the barrier to resistance is high enough, resistant viral variants are not selected and do not grow; if it is not, they rapidly fill in the replication space and become the dominant (or exclusive) viral population associated with high-level replication.

The main components of the barrier to resistance in vivo are: (i) the “genetic barrier to resistance”, defined as the number of amino acid substitutions needed for a viral variant to acquire full resistance to the drug in question. If a single substitution is sufficient to confer high-level resistance, then the drug is considered to have a low genetic barrier to resistance, while the need for three or more substitutions represents a high genetic barrier; (ii) the “in vivo fitness” of the resistant viral variant population, defined as its ability to survive and grow in the replicative environment; (iii) drug exposure, defined as the drug concentration achieved in vivo relative to the 50% and 90% inhibitory concentrations (IC) and efficient concentrations (EC) [1].


A number of direct acting antiviral (DAA) drugs are in development for the treatment of chronic hepatitis C virus (HCV) infection. Two NS3/4A protease inhibitors, telaprevir and boceprevir, have been recently approved in combination with pegylated interferon (IFN)-α and ribavirin for the treatment of genotype 1 chronic hepatitis C [2], [3], [4], [5]. Other DAAs are at various stages of preclinical to late clinical development. They can be schematically classified into two groups, according to their barrier to resistance. Drugs with a low barrier to resistance include first-generation NS3/4A protease inhibitors (e.g. telaprevir and boceprevir and numerous other molecules in development), NS5A inhibitors, and non-nucleoside inhibitors (NNI) of HCV RNA-dependent RNA polymerase (RdRp) [6]. Their administration as monotherapies has been reported to be associated with early virological breakthroughs due to the selection and subsequent outgrowth of fit resistant viral populations carrying one or several substitutions that confer resistance to the drug [7], [8], [9]. Drugs with a high barrier to resistance include nucleoside/nucleotide analogue inhibitors of HCV RdRp, cyclophylin inhibitors (drugs that target a host cell protein involved in viral replication), and potential second-generation NS3/4A protease inhibitors. They can be administered alone for weeks without any virological breakthrough due to resistance in the majority of cases [10], [11].


Prevention of resistance, particularly when drugs with a low barrier to resistance are used, is based on the combination of several molecules that are potent and have no cross-resistance. No cross-resistance means that each member of the combination is fully active on viruses that are resistant to the others. This concept was the basis for combining NS3/4A protease inhibitors (or other DAAs with a low barrier to resistance) with pegylated IFN-α and ribavirin. Unfortunately, in patients who do not respond adequately to IFN-α and ribavirin, treatment fails and as a result DAA-resistant variant populations grow [1]. In order to cure infection without selecting for resistance, it is also possible to combine potent DAAs without cross-resistance, with the double goal of achieving better antiviral efficacy and substantially increasing the barrier to resistance. Attempts with combinations of drugs with low barriers to resistance, such as an NS3/4A protease inhibitor with an NS5A inhibitor, or an NS3/4A protease inhibitor with an NNI, have been disappointing [12], [13]. Although cure was achieved in a few patients receiving the former combination [14], the rates of failure due to selection of viral variants bearing substitutions at both drug target sites were frequent in these studies, suggesting that the barrier to resistance of a combination of two HCV drugs with low barriers to resistance is not dramatically greater than that of each drug alone.


There are four distinct groups of NNI inhibitors of HCV RdRp in development. Each targets a different allosteric site at the surface of the enzyme, and they have been reported to have different resistance profiles in vitro, without cross-resistance. Thus, although targeting the same viral enzyme, NNIs from different classes could theoretically be combined together. In this issue of the Journal of Hepatology, Delang et al. report their assessment of the antiviral potencies and resistance selection profiles of members of three of the four NNI groups [15]. These compounds were tested alone and in double or triple combination in replicon-harboring Huh7 cell lines, the usual model for this type of experiments. The authors confirmed the low barrier to resistance of each NNI alone and the lack of cross-resistance between them. They also showed that these drugs have additive antiviral effects in vitro.


When a stepwise, long-term procedure was used, the authors were able to select variants resistant to each pair-wise combination, which carried amino acid substitutions conferring high-level resistance to both tested NNIs on the same strain. Triple resistant replicons were also generated, starting from a replicon that was already resistant to two NNIs and was subsequently exposed to the third one. The triple-resistant replicons harbored substitutions conferring resistance to the three drugs tested. It was also cross-resistant with the fourth class of NNIs, not used in the experiments [15]. Whether such triple resistant variants naturally preexist in infected patients remains unknown. Short-term replication models, such as replicons in Huh7 cell lines, could underestimate the extent of HCV variability encountered in patients who have been infected for decades. Indeed, it has been recently suggested, based on mathematical modeling, that in HCV-infected patients, all possible single and double mutants are generated multiple times each day, all viable single and double mutants that confer drug resistance preexist and may compete with the wild-type virus during therapy, and triple mutants can be selected by sequential mutations when single or double mutants replicate [16]. It is therefore highly likely that HCV variants that are resistant to three drugs preexist at baseline in a substantial proportion of patients, or that they can be generated through replication of double-resistant viruses.


Resistance to DAAs is often feared as the main cause of treatment failure with new HCV therapies. This is not the case with the triple combination of a DAA with pegylated IFN-α and ribavirin, during which treatment failure results of an inadequate response to IFN-α that favors the outgrowth of resistant viral variants selected by the DAA [1], [2], [3], [4], [5]. In contrast, control of resistance will be key during the era of all-oral, IFN-free regimens. Indeed, antiviral potency and a high barrier to resistance are required to ensure that inhibition of HCV production is sustained for a sufficient amount of time in order for every infected cell to clear the remaining viruses. If any viral population is not controlled by the drug combination, it replicates, is produced, infects new cells and leads to treatment failure. Intuitively, the best way to prevent such failure is to include at least one drug with a high barrier to resistance, such as a nucleoside/nucleotide analogue or a cyclophylin inhibitor, in any combination of HCV DAAs. However, these drugs have not yet reached the market and the results of long-term combination studies including one or two nucleoside/nucleotide analogue(s) are awaited.


What will be the role of NNIs in this context? Recent results with the two most advanced in development NNIs, tegobuvir and filibuvir, have been disappointing: no difference was observed between the triple combination of different doses of the NNI with pegylated IFN-α and ribavirin vs. pegylated IFN-α and ribavirin alone [17], [18]. Nevertheless, this failure appears to be principally related to the lack of antiviral potency of these compounds rather than to their barrier to resistance, which is not fundamentally different from that of telaprevir or boceprevir. It is therefore possible that more potent NNIs could prove to be useful in combination with pegylated IFN-α and ribavirin.


What the study by Delang et al. teaches us is that combinations of NNIs are unlikely to be helpful, even if the molecules belong to different classes, have different target sites and no cross-resistance. In vitro results in the replicon system have proven to be accurate in predicting resistance in vivo; thus, single, double, and triple-resistant variants are likely to be selected early by NNI combinations in infected patients. How will we use NNIs in IFN-free regimens in the future? Ideally, in combinations including at least one drug with a high barrier to resistance (e.g. a nucleoside/nucleotide analogue, a cyclophylin inhibitor, or a second-generation NS3/4A protease inhibitor with an improved resistance profile compared to first-generation ones). Nevertheless, if these drugs are potent enough, they should, at least theoretically, be able to block virus production without resistance emergence for long enough for the virus to be cleared by host cells without the need for other drugs. If this is the case, drugs with a narrow genotype coverage and a low barrier to resistance, such as NNIs, may not be absolutely required in the HCV drug armamentarium. This question will be solved by ongoing and future clinical trials.


Overall, trial designers and clinicians should remember that, if resistance is not a major threat in patients treated with the triple combination of a DAA with pegylated IFN-α and ribavirin, since the final outcome depends mainly on the IFN response, its prevention will be key in the design of all-oral treatment strategies based on DAA combinations. Only combinations with a high enough barrier to resistance should be envisaged, as they are the only ones that can ensure sustained inhibition of viral production for the time needed for host cells to get rid of the virus. As in any war, the final victory depends on the allies you chose. Our mission is now to find the best alliance to keep the invaders out. This is the price to pay for a peaceful world, i.e. a world without hepatitis C.

Conflict of interest

The author has received research grants from Gilead and Roche. He has served as an advisor for Abbott, Anadys, Biotica, Boehringer-Ingelheim, Bristol-Myers Squibb, DebioPharm, Gilead, Glaxo-SmithKline, Idenix, Janssen-Cilag, Madaus-Rottapharm, Schering-Plough/Merck, Novartis, Pfizer, Pharmasset, Roche, Vertex and Virco.

References

1. Pawlotsky JM. Treatment failure and resistance with direct-acting antiviral drugs against hepatitis C virus. Hepatology. 2011;53:1742–1751
2. Bacon BR, Gordon SC, Lawitz E, Marcellin P, Vierling JM, Zeuzem S, et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1207–1217
3. Jacobson IM, McHutchison JG, Dusheiko G, Di Bisceglie AM, Reddy KR, Bzowej NH, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364:2405–2416
4. Poordad F, McCone J, Bacon BR, Bruno S, Manns MP, Sulkowski MS, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1195–1206
5. Zeuzem S, Andreone P, Pol S, Lawitz E, Diago M, Roberts S, et al. Telaprevir for retreatment of HCV infection. N Engl J Med. 2011;364:2417–2428
6. Pawlotsky JM, Chevaliez S, McHutchison JG. The hepatitis C virus life cycle as a target for new antiviral therapies. Gastroenterology. 2007;132:1979–1998
7. Sarrazin C, Kieffer TL, Bartels D, Hanzelka B, Muh U, Welker M, et al. Dynamic hepatitis C virus genotypic and phenotypic changes in patients treated with the protease inhibitor telaprevir. Gastroenterology. 2007;132:1767–1777
8. Gao M, Nettles RE, Belema M, Snyder LB, Nguyen VN, Fridell RA, et al. Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect. Nature. 2010;465:96–100
9. Mori J, Hammond JL, Srinivasan S, Jagannatha S, van der Ryst E. Genotypic characterisation of filibuvir (PF-00868554) resistance in patients receiving four weeks co-administration of filibuvir with pegIFN/RBV (12-week analysis). J Hepatol. 2010;52:S15
10. Le Pogam S, Seshaadri A, Ewing A, Kang H, Kosaka A, Yan JM, et al. RG7128 alone or in combination with pegylated interferon-alpha2a and ribavirin prevents hepatitis C virus (HCV) replication and selection of resistant variants in HCV-infected patients. J Infect Dis. 2010;202:1510–1519
11. Coelmont L, Gallay P, Bobardt M, Kaptein S, Paeshuyse J, Vliegen I, et al. Particular in vitro anti-HCV activities and resistance profile of the cyclophylin inhibitor DEBIO-025. J Hepatol. 2009;50:S36
12. Zeuzem S, Buggisch P, Agarwal K, Manns MP, Marcellin P, Foster GR, et al. Dual, triple, and quadruple combination treatment with a protease inhibitor (GS-9256) and a polymerase inhibitor (GS-9190) alone and in combination with ribavirin (RBV) or PegIFN/RBV for up to 28 days in treatment-naïve, genotype 1 HCV subjects. Hepatology. 2010;52:400A
13. Lok AS, Gardiner DF, Lawitz E, Martorell C, Everson GT, Ghalib RH, et al. Combination therapy with BMS-790052 and BMS-650032 alone or with PegIFN/RBV results in undetectable HCV RNA through 12 weeks of therapy in HCV genotype 1 null responders. Hepatology. 2010;52:877A
14. Lok A, Gardiner D, Lawitz E, Martorell C, Everson G, Ghalib R, et al. Quadruple therapy with BMS-790052, BMS-650032 and PEG-IFN/RBV for 24 weeks results in 100% SVR12 in HCV genotype 1 null responders. J Hepatol. 2011;54:S536
15. Delang L, Vliegen I, Leyssen P, Neyts J. In vitro selection and characterization of HCV replicons resistant to multiple non-nucleoside polymerase inhibitors. J Hepatol. 2011;
16. Rong L, Dahari H, Ribeiro RM, Perelson AS. Rapid emergence of protease inhibitor resistance in hepatitis C virus. Sci Transl Med. 2010;2:30ra32
17. Jacobson I, Pockros PJ, Lalezari J, Lawitz E, Rodriguez-Torres M, DeJesus E, et al. Virologic response rates following 4 weeks of filibuvir in combination with pegylated interferon alfa-2a and ribavirin in chronically-infected HCV genotype 1 patients. J Hepatol. 2010;52:S465
18. Lawitz E, Jacobson I, Godofsky E, Foster GR, Flisiak R, Bennett M, et al. A phase 2B trial comparing 24 to 48 weeks treatment with tegobuvir (GS-9190)/PEG/RBV to 48 weeks treatment with PEG/RBV for chronic genotype 1 HCV infection. J Hepatol. 2011;54:S181