March 15, 2012

NS5A inhibitors: Picomolar power to combat hepatitis C virus?

March 15, 2012 8:07 am

NS5A inhibitors: Picomolar power to combat hepatitis C virus? Dr Paul Targett-Adams, Principal Scientist at Medivir AB.

Hepatitis C virus (HCV) is a global health issue; approximately 170 million individuals are infected worldwide and are at risk of developing life-threatening liver diseases (Lavanchy, 2009). There is no vaccine and treatment options are limited and very challenging for patients. Despite the recent approval of new direct-acting antiviral (DAA) medicines, which target the virus-encoded protease, the backbone of current therapy still includes interferon. Interferon has to be self-administered by injection and is associated with nasty side effects that significantly diminish the quality of life of patients required to take it. One need only view the harrowing YouTube video diary documenting a plight of an HCV-positive teenager undergoing interferon treatment (De Lisser, 2009) to realize that new treatment regimes that do not require interferon are urgently needed to alleviate the suffering of millions of patients. To achieve this, combinations of distinct DAA classes will likely be used to attack the virus from different angles and drive it into submission. Encouragingly, the HCV pipeline is populated with over 50single DAAs in clinical development (Pawlotsky, 2012). Of course, only a subset will make it to market and the most advanced molecules in clinical development will likely still require an interferon backbone when they are first licensed for use, especially in patients infected with HCV genotype 1. However, the race is most definitely on to develop the first interferon-free therapies and we’ve already seen promising data from dual DAA combination trials without interferon (Chayama et al., 2012; Lok et al., 2012), and interferon-free triple DAA combination trials are now also recruiting. Nonstructural protein 5A (NS5A) inhibitors feature prominently in DAA combination trials, but what are they and what’s so special about them?!

NS5A inhibitors are chemical compounds that target the HCV-encoded NS5A gene product; a rather enigmatic non-enzymatic protein, which is essential for viral genome replication and virus assembly. It’s a key modulator of the HCV life cycle but we really don’t know what its exact functions are! Hence, screening for molecules that directly target NS5A is incredibly difficult. However, a clever ‘chemical genetics’ strategy combined with a pinch of serendipity enabled Bristol-Myers Squibb to discover and develop a NS5A inhibitor called BMS-790052 (Lemm et al., 2011; Gao et al., 2012); a paradigm-shifting HCV DAA, subsequently renamed daclatasvir and now under phase III clinical evaluation. Although their exact mechanism of action remains unknown, N5A-targeting molecules probably function by deregulating the intricate relationship between NS5A and intracellular HCV replication sites (Targett-Adams et al., 2011). NS5A inhibitors have now become a super-hot focus for HCV drug development and one need only list some of their very impressive headline-grabbing stats to appreciate why:

1. Only picomolar quantities of NS5A inhibitors are required to inhibit HCV replication in cell culture-based models. Let’s put that into context; in comparison to the current licensed HCV protease inhibitors, about a thousand-foldlessNS5A inhibitor molecules are required to elicit equivalent levels of HCV inhibition in cell culture. They are probably the most potent antiviral molecules ever discovered.
2. NS5A-targeting molecules can suppress replication of all HCV genotypes i.e. they display pan-genotypic activity.
3. The resistance profiles of NS5A inhibitors do not overlap with those of other DAAs, which means, in theory, they could partner any other DAA mechanistic class in combination regimens.
4. The pharmacokinetic properties of NS5A-targeting molecules suggest they are amenable to once-daily dosing in patients and, to date, they appear to be safe in humans.
5. Most importantly, they work! We’ve seen some impressive suppression of viral loads in HCV-infected patients treated with daclatasvir (Gao et al., 2010; Nettles et al., 2011; Chayama et al., 2012; Lok et al., 2012).

However, as remarkable as these molecules are, they are not equally effective in all patient groups – they have an Achilles heel. Specifically, current NS5A inhibitors are particularly susceptible to certain drug-resistant virus variants in patients infected with HCV genotype 1a, which leads to viral breakthrough during treatment. Take daclatasvir as an example, a single nucleotide substitution in the HCV genotype 1a genome can result in an amino acid change from tyrosine to asparagine at position 93 in the NS5A protein sequence, which renders HCV 47,000-fold less susceptible to daclatasvir (Fridell et al., 2010). A combination of 2 amino acid changes in the NS5A protein coding sequence of genotype 1a requires micromolar concentrations of daclatasvir to inhibit HCV replication (Fridell et al., 2010); well beyond the concentrations of the drug achievable in humans! This liability to resistance mutations in NS5A is less pronounced for genotype 1b but remains evident; hence, NS5A inhibitors feature a low genetic barrier to resistance. Why is this problematic? Well, HCV exhibits astounding levels of genetic diversity in chronically-infected individuals, which is driven by a high replicative ability of the virus in the liver(up to a trillion HCV particles can be produced in a chronically-infected individual per day) compounded by an error-prone nature of genome synthesis. As a result, it is likely that every possible single (and probably double) mutation in the virus genome is generated at least once a day. Basically, all the mutations that render HCV resistant to any 1 DAA probably already exist in patients even before they are ever exposed to a specific HCV antiviral drug! Drug resistance is the scourge of HCV drug development and is certainly not limited to just HCV NS5A inhibitors. However, therapeutic regimens composed of a combination of DAAs from different mechanistic classes will have the power to combat HCV drug resistance and the true benefit of NS5A inhibitors will likely be realised as components of tailored HCV DAA drug cocktails. Here, they can utilize their potency to drive down virus replication within a relative safety net afforded by the presence of other HCV DAAs, so that resistance to any one DAA can be quashed by others present in the same combination. Many major pharmaceutical companies involved in HCV drug development have a NS5A inhibitor in their arsenal and the appetite for these molecules is still strong, as evidenced by the recent acquisition of Enanta’s NS5A inhibitor (EDP-239) by Novartis in a deal worth $440 million.

NS5A inhibitors are indeed remarkable molecules; enigmatic, powerful, and will likely be key components of future combination therapies designed to alleviate the suffering of millions of patients infected with HCV. Continued research and development will enable the discovery of improved molecules with a superior genetic barrier to resistance. The future is looking brighter; HCV is a chronic virus infection that we can ultimately cure, and NS5A inhibitors could play a pivotal role.

1. Chayama K et al. Dual therapy with the nonstructural protein 5A inhibitor, daclatasvir, and the nonstructural protein 3 protease inhibitor, asunaprevir, in hepatitis C virus genotype 1b-infected null responders. Hepatology (2012) 55:742-8

2. De Lisser J. My story of C. YouTube (2009)

3. Fridell RA et al. Resistance analysis of the hepatitis C virus NS5A inhibitor BMS-790052 in an in vitro replicon system. Antimicrob Agents Chemother (2010) 54:3641-50.

4. Gao M et al. Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect. Nature (2010) 465:96-100.

5. Lavanchy D. The global burden of hepatitis C. Liver Int (2009)29 Suppl 1:74-81.

6. Lemm JA et al. Discovery of potent hepatitis C virus NS5A inhibitors with dimeric structures. Antimicrob Agents Chemother (2011) 55:3795-802.

7. Lok AS et al.Preliminary study of two antiviral agents for hepatitis C genotype 1. N Engl J Med(2012)366:216-24.

8. Nettles RE et al. Multiple ascending dose study of BMS-790052, a nonstructural protein 5A replication complex inhibitor, in patients infected with hepatitis C virus genotype 1. Hepatology (2011) 54:1956-65.

9. Pawlotsky JM. New Antiviral Agents for Hepatitis C. F1000 Biol Rep (2012) 4:5.

10. Targett-Adams P et al. Small molecules targeting hepatitis C virus-encoded NS5A cause subcellular redistribution of their target: insights into compound modes of action. J Virol (2011) 85:6353-68.

About the Author


Dr Paul Targett-Adams

After completing his PhD on the molecular biology of herpes simplex type 1 DNA packaging at the MRC Virology Unit at Glasgow in 2001, he embarked upon his post-doctoral research career focusing upon the intricate molecular details of hepatitis C virus (HCV) RNA replication. Later, in 2008, he joined the Antivirals Research Unit at Pfizer UK to continue his work on HCV with the added bonus of directly translating his research knowledge to investigating HCV mechanisms amenable to drug discovery programs. It was at Pfizer that his interest in HCV NS5A inhibitors, an exciting and intriguing new class of anti-HCV molecules was first piqued. In 2012 he joined Medivir AB in Stockholm as a Principal Scientist committed to discovering and developing novel antiviral medicines to combat a range of virus infections of global medical significance; including, of course, HCV. He can be contacted through LinkedIn or on .


A Silent Epidemic: Why Chronic Hepatitis B Matters CME

From Medscape Education Family Medicine

Robert P. Perrillo, MD; John W. Ward, MD

CME Released: 03/14/2012; Valid for credit through 03/14/2013


Slide 1.

Robert Perrillo, MD: Hello. I am Bob Perrillo, Chair of the American Association for the Study of Liver Diseases (AASLD) Hepatitis B Special Interest Group and clinical hepatologist at Baylor University Medical Center in Dallas.

I am pleased to welcome you to this CME-certified activity titled "A Silent Epidemic: Why Chronic Hepatitis B Matters."

I am particularly delighted to be joined today by Dr John Ward, who is the director of the Division of Viral Hepatitis at the National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention at the Centers for Disease Control and Prevention (CDC) in Atlanta.

John, why should healthcare providers in the United States be concerned about hepatitis B virus (HBV) infection?


Slide 2.

John Ward, MD: Although HBV infection is a common health problem globally and in the United States, it is known as the silent epidemic because the public and many providers are unaware of its scope. Transmission continues to be a problem here in the United States. Approximately 370 million people worldwide have HBV infection, which causes approximately 660,000 deaths every year. Acute infection may lead to chronic infection that over decades can lead to severe liver disease, liver cirrhosis, and hepatocellular carcinoma (HCC), or primary liver cancer.


Slide 3.

Liver cancer is the second leading cause of cancer deaths worldwide,[1] and a major cause of those deaths from liver cancer is HBV infection. Hepatitis B is more common in some parts of the world than others; it is a particularly large problem in Asia -- 1 of the most heavily populated areas on the planet -- as well as Sub-Saharan Africa, some areas of South America, and other regions. Persons who migrate from those regions to the United States bring hepatitis B with them. The CDC estimates that up to 1.4 million persons are living with hepatitis B infection in the United States and are at risk for cirrhosis and liver cancer. In addition, approximately 30,000 to 40,000 new infections occur every year in the United States..

Dr Perrillo: It is a worldwide health issue of great importance, and the United States is clearly affected by the effects of immigration from these areas of high endemicity. It is quite clear that clinicians in the United States can benefit from a global perspective of this serious problem. John, what can we do to prevent transmission?


Slide 4.

Dr Ward: The hepatitis B virus that causes hepatitis B disease is transmitted through blood contact in healthcare settings, among injection-drug users, and in the household setting through everyday exposures to small amounts of blood and through sexual contact among adolescents and adults. Importantly, an infected mother can transmit the virus to her infant at birth.


Slide 5.

Fortunately, we have safe and highly effective vaccines to prevent transmission via all of these routes, and our vaccine recommendations are designed to seize those opportunities to prevent transmission. We at the CDC recommend that all newborns in the United States receive the initial birth dose of HBV vaccine before leaving the birthing hospital to prevent acquisition of HBV from the infected mother. We recommend that all children receive the 3-dose vaccine series that begins in the hospital and is completed in the pediatrician's office. [Eds. note: A fourth dose is permissible if a combination vaccine that includes hepatitis B is administered after the birth dose.] The vaccines are highly effective and appear to provide protection for decades. We also recommend vaccination for adults who engage in high-risk sexual behaviors, adults who are current or recent injection-drug users, and men who have sex with men. We also recognize that healthcare workers are at high risk for occupational transmission, and we recommend vaccination for all healthcare workers.

Patients who have only recently been recognized to be at increased risk for hepatitis B transmission are persons with diabetes (in whom transmission can occur when infection control practices are not followed during blood glucose monitoring). The CDC has investigated a number of outbreaks of hepatitis B among persons with diabetes because infection control is not followed in places such as residential care facilities and medical facilities. In November 2011, the CDC recommended that all persons with diabetes younger than 60 years be vaccinated against hepatitis B. Because the vaccine is less effective in persons 60 years and older, it should be given at the discretion of the healthcare provider. I do want to emphasize the new recommendation that persons with diabetes should be offered hepatitis B vaccine. This new recommendation is part of the 2012 Recommended Adult Immunization Schedule.

Dr Perrillo: That is important new information.

One of the major challenges facing healthcare providers, as identified in the 2010 Institute of Medicine (IOM) report,[2] is the need to more conscientiously screen for hepatitis B infection. John, would you describe for us briefly the CDC screening recommendations?


Slide 6.

Dr Ward: We have an intervention available to us to prevent infection -- vaccination -- and we have interventions to prevent disease progression for persons living with hepatitis B infection -- screening and linkage to care. As treatments have improved over the past 10 to 15 years, the benefits of screening (ie, knowing your status, obtaining timely care) have increased. In 2008, the CDC for the first time issued national recommendations as to who should be screened [for HBV]. The recommendations align with the epidemiology of hepatitis B and the populations that have the highest prevalence of chronic hepatitis B infection. One group includes persons born in countries such as in Asia and Africa that have a high prevalence of hepatitis B and who live in the United States. Some Asian populations in the United States have a staggering 8% to 10% prevalence of chronic hepatitis B infection[3]; as a result, their liver disease and liver cancer rates are much higher than in other populations.To further compound the issue, many of these Asian and African HBV carriers may be uaware of their HBV status and may not have access to health care, so it is truly a health disparity for those patient populations. Screening is also recommended for men who have sex with men, injection-drug users, and persons who are about to begin immunosuppressive therapy.

One question we are often asked at the CDC is from clinicians who want guidance on how they should interpret results of the various tests for HBV infection. Bob, would you go over the various tests that are available to a clinician to screen someone for hepatitis B, what they measure, and how they should be used?


Slide 7.

Dr Perrillo: Unfortunately, this continues to be an area of confusion for clinicians. Hepatitis B surface antigen (HBsAg) is the basic test that shows whether a patient is infected; notably, HBsAg positive patients may be acutely or chronically infected. Antibody to the hepatitis B core (anti-HBc) can be a marker for ongoing infection as well as an indicator of past infection, and a small percentage of patients with isolated anti-HBc actually have low levels of HBV DNA in their serum; we call this occult infection. Antibody to the surface antigen (anti-HBs) is a neutralizing antibody, and this is the antibody that develops after vaccination and after successful immunologic recovery from either acute or chronic hepatitis B. It is important to note that HBsAg negative individuals who appear to have recovered from infection may continue to have small amounts of HBV DNA in their liver cells and other tissues, perhaps indefinitely, with the lowest amounts of HBV DNA occurring in individuals who have both anti-HBc and anti-HBs.

Many of the HBsAg negative patients we see who have recovered from hepatitis B have both anti-HBc and anti-HBs. This group of patients is at the highest state of immunologic control over future virus replication and accordingly is least susceptible to future reactivation of HBV. The patient who has isolated anti-HBc is a bit more worrisome and controversial because we do not routinely test these people for HBV DNA levels and some may have occult viremia. This factor and absence of the neutralizing antibody (anti-HBs) places them at greater risk for reactivation in the future, particularly during immunosuppressive therapy.

Dr Ward: It suggests that patients who are positive for HBsAg are actively replicating the virus.

Dr Perrillo: It may not be detectable in serum, but it is a protein. It is transcribed from the viral genome, so yes, there has to be some DNA and some replication.

Dr Ward: I have tried to describe the populations that from a public health perspective we feel are important to be screened and linked to care. Perhaps from a clinical perspective, Bob, you can describe the next steps to protect the health of the patient who has been screened and found to have hepatitis B.


Slide 8.

Dr Perrillo: Whenever an HBsAg positive patient comes to our office, we think of a possible need for treatment to forestall disease progression and to prevent the long-term complications of infection. Recently, longitudinal cohort studies have shown that the level of HBV DNA n the blood predicts the relative risk for developing complications, such as cirrhosis and HCC. In addition, data show lower rates of decompensation, liver failure, and HCC in patients with advanced fibrosis who undergo antiviral treatment compared with patients who are not treated or who are treated with placebo.[34] The data strongly suggest that maintenance treatment to suppress high rates of viral replication in older HBsAg carriers may prevent long-term complications.


Slide 9.

Additionally, when you see an HBsAg carrier in the office, you can set up surveillance for HCC with a liver ultrasound study and with alpha-fetoprotein testing every 6 months for those over the age of 40 or those with cirrhosis. The AASLD has issued very clear guidelines about providing HCC surveillance in HBsAg carriers.[4]

I mentioned reactivation due to immunosuppressive therapy, but we can only prevent this complication of immunosuppressive drugs by screening the patient for HBV and evaluating their level of risk. Furthermore, the initial office visit also is the best time to talk about vaccinating household contacts, and to educate the patient about the potential importance of hepatitis B; sadly, the patient may have been told by other providers that HBV infection is not something of great concern. These providers are typically dealing with the patient's other health issues that may appear to have greater priority.

When you see a patient in the clinic who has HBV infection, you should also ask whether other people in the household have been tested. Very often the patient does not know the results of the household contacts' tests or whether the household contacts were tested at all. We should always get this point across that household members need to be tested, particularly if perinatal transmission is suspected in your patient (in which case there might also be an infected sibling who has not yet been tested). The benefits that we just outlined could apply to other household members as well.

Dr Ward: Bob, you mention screening persons who are candidates for immunosuppressive therapy. I wonder if you could explain why it is important to screen that population for hepatitis B infection.


Slide 10.

Dr Perrillo: In our clinic, we see reactivation in patients who have not been screened for HBV and have undergone immunosuppressive therapy, which allows the virus to replicate unimpeded by the host immune response. We see an immunologic reconstitution effect when immunosuppressive therapy is stopped, and that is often followed by a flare of hepatitis because of aggressive cellular immune attack on hepatocytes that have become more heavility infected. What is particularly dramatic is a flare that is superimposed on severe underlying liver disease and advanced fibrosis, because it can lead to liver failure and death.

The population of patients at risk for HBV reactivation due to immunosuppressive therapy stretches far beyond those undergoing cancer chemotherapy; there are many thousands of patients on other, seemingly more benign immunosuppressive agents, such as tumor necrosis factor-alpha inhibitors, which have also been linked to reactivation. Again, the message is to screen patients before exposure to such drugs and then, if the patient is positive for HBsAg or isolated anti-HBc, you can refer the patient to a specialist who can initiate prophylactic antiviral therapy. The good news is that antiviral therapy, given for a few days to weeks prior to the initiation of immunosuppressive therapy, can prevent the vast majority of these reactivation events from occurring; that is really important to keep in mind.

Dr Ward: Yes, it is an important opportunity to intervene.

Dr Perrillo: John, we have indicated today that hepatitis B is a potentially serious disease both globally and in the United States that is best dealt with by conscientious attention to vaccination, screening those at risk, and linking patients who are HBsAg positive to care. John, can you tell me the health priority plan for hepatitis B, and how are we going to deal with this in the United States in the future?


Slide 11.

Dr Ward: I am happy to report that there has been a lot of attention paid to hepatitis B over the past several years at the policy level here in the United States. In 2010, the IOM released a report calling attention to hepatitis B and to C; the IOM recognized them as underappreciated health problems with missed opportunities of prevention, care, and treatment that resulted in unnecessary loss of life and quality of life.[2] In its report, the IOM issued several recommendations that the US government could take to improve hepatitis prevention, care, and treatment; this led the Department of Health and Human Services (DHHS) to release a plan for viral hepatitis in May 2011. The plan includes a number of activities that the agencies within that department -- including the National Institutes of Health, Food and Drug Administration, and CDC -- could initiate to improve education for providers as well as communities (particularly those experiencing health disparities) in order to improve the opportunities for testing and linkage to care and treatment. Other activities include strengthening surveillance, so that we can better grasp the transmission and burden of disease, and identifying individuals who are not getting preventive services and care services. We have set a goal of eliminating transmission through vaccination, and the plan outlines opportunities to realize that goal, while recognizing particular groups at risk for multiple forms of hepatitis. The plan also recognizes the problem of patient safety and transmission in the healthcare setting. I am happy to report that the plan is available from the DHHS. It is very dynamic, and it really sets hepatitis as a new health priority for the nation.


Slide 12.

Dr Perrillo: It is resoundingly clear, then, that although hepatitis B is a serious clinical and public health issue, it is also something that we can prevent and treat. Treatments have advanced markedly over the past 10 to 15 years, and we now have oral antiviral agents that are very safe and can be given long-term to suppress viral replication. I believe these agents are going to lower the frequency of the complications associated with HBV. It is a very important message, but you can only identify the patients who will benefit most from these therapies through diligent HBV screening.

Dr Ward: Right.

Dr Perrillo: Our message today is that we need to vaccinate patients at risk for HBV, we need to screen those people that we think might be HBV-positive, and we need to link the HBV-positive patients to care. We have to be more active in our surveillance, per the IOM report. The future sounds a bit better because we are beginning to recognize hepatitis B as a serious health priority in this nation and identify where the gaps have been in our surveillance and linkage to care. It is imperative to appreciate the deficiencies in dealing with this serious health issue in order to devise practical and meaningful solutions, wouldn't you agree?

Dr Ward: I could not agree more. We have a good vaccine. We can prevent transmission. We have screening tests and guidelines for direct screening to the populations most in need. People can only benefit from these advances in treatment if we get them screened and into quality care. Both in public health and in clinical medicine, we should realize these opportunities can translate into health benefits for the people in the United States.


Slide 13.

Dr Perrillo: Thank you, John, for your interesting comments and in-depth discussion today, and I want to thank you all for participating in this activity.

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GPs urged to investigate raised ALT levels for hepatitis C


By David Swan | 15 Mar 2012

GPs should follow up all patients with a mildly raised alanine aminotransferase level to rule out hidden hepatitis C infection, say researchers.

The Dutch study looked at the prevalence of hidden hepatitis C infection in primary care patients and a cut-off for investigating raised ALT levels.

The researchers identified patients referred by their GP for liver enzyme testing with a mildly elevated ALT test result (30-100 IU/l) and grouped them by the different ranges of ALT elevation – 30-50 IU/l, 50-70 IU/l and 70-100 IU/l. Each group contained 250 samples, and each patient was tested for hepatitis C and hepatitis B.

They found prevalence of hepatitis C was not elevated in patients with an ALT level of 30-50 IU/l, but the prevalence of positive anti-hepatitis C test results was 2.0% in the 50-70 IU/l ALT level group and 1.2% in those with an ALT level of 70-100 IU/l.

They concluded that in primary care patients with an ALT elevation between 50 IU/l and 100 IU/l the risk of hepatitis C infection was substantially elevated.

Study lead Professor Charles Helsper, assistant professor and lecturer for GP-specialty training at Utrecht University, said: ‘It is recommended that in all patients with an ALT elevation of 50 UI/l-100 UI/l, particularly those for whom no clear explanation for the ALT elevation is found, diagnostic follow-up for hepatitis C is performed.'

British Journal of General Practice 2012; 62: e212-e216


Public release date: 15-Mar-2012

Contact: Travis Taylor
European Association for the Study of the Liver

The European Association for the Study of the Liver (EASL) and the European Organisation for Research and Treatment of Cancer (EORTC) today publish their first joint Clinical Practice Guidelines (CPGs) on the management of hepatocellular carcinoma (HCC).(1) The EASL-EORTC guidelines define the use of surveillance, diagnosis and therapeutic strategies recommended for patients with HCC.

HCC is the most common form of liver cancer, representing more than 90% of primary liver cancers and an increasing global health burden. It is estimated that, by 2020, the number of cases will reach 78,000 in Europe (up from 65,000 in 2008) and 27,000 in the US (up from 21,000 in 2008). Affecting 2.4 times more men than women, approximately 90% of HCCs are associated with a known underlying risk factor -- the most frequent including chronic viral hepatitis (types B and C), alcohol intake and aflatoxin(2) exposure.

Lead author Professor Josep M Llovet said: "Despite the availability of effective surveillance and treatment strategies for HCC, the proportion of patients currently receiving these interventions is suboptimal. When considered in light of HCC's growing European and global incidence, it is critical that measures are implemented to increase access to surveillance, early diagnosis and effective treatment."

Based on a systematic review of existing literature, the CPGs provide best practice recommendations on a number of key areas:

  • Epidemiology, risk factors and prevention
  • Surveillance, including target populations
  • Diagnosis, including non-invasive diagnosis, pathological diagnosis, molecular diagnosis and assessment of disease extension
  • Staging systems, including the Barcelona-Clinic Liver Cancer (BCLC) classification (outcome prediction and treatment allocation) and molecular classification of HCC
  • Surgical, loco-regional and medical treatment update, including latest advances and methods, and the endorsement of treatment stage migration
  • Clinical trial design
  • Assessment of response, and recommendation of the modified RECIST (mRECIST) criteria

The guidelines also identify major unmet needs for advancing HCC research and, ultimately, contributing to improved patient care, recommending physicians, investigators, health policy agencies, the pharmaceutical industry and care providers prioritise devoting future resources to:

  • Evaluating adjuvant therapies after resection/local ablation and the benefits of combining molecular therapies with local ablation and loco-regional treatments
  • Exploring downstaging(3) strategies to rescue patients with HCCs beyond conventional Milan criteria
  • Developing effective treatment packages for advanced tumours and second-line therapies
  • Robust cost-benefit and health-economic analysis/studies to facilitate clinical decision-making
  • Providing adequate quality of life assessment tools, as quality of life is a relevant end-point for research studies

Professor Llovet said: "The HCC CPGs outline a clear need for investment in research, through which it will be possible to address important future clinical goals and advances, such as biobanking (the considered collection of tissue and serum samples in research studies) and personalised medicine."

Commenting on the CPGs, EASL Secretary General Professor Mark Thursz said: "EASL is dedicated to promoting hepatology research and education to improve the worldwide treatment of liver disease. As there have been several key clinical and scientific advances over the past decade, these guidelines update the recommendations reported by the EASL HCC panel of experts in 2001. EASL hopes these new HCC guidelines provide clinicians with the most up-to-date, evidence based methods for the management of affected patients."


To be simultaneously published in the Journal of Hepatology (Vol. 56 No. 4 April, 2012) and the European Journal of Cancer (Vol. 48 No. 5 March, 2012), the EASL-EORTC joint CPGs on the management of HCC will also be presented during a session of the International Liver CongressTM 2012 in Barcelona (1530, Saturday, April 21st).

About EASL

EASL is the leading European scientific society involved in promoting research and education in hepatology. EASL attracts the foremost hepatology experts and has an impressive track record in promoting research in liver disease, supporting wider education and promoting changes in European liver policy.

EASL's main focus on education and research is delivered through numerous events and initiatives, including:

About the EORTC

The EORTC is a unique organization – a vibrant example of the fact that science and research know no national boundaries. Established in 1962, the EORTC is a non-profit research organization operating as an international association under Belgian law.

The EORTC currently links a network of more than 2,500 pre-clinical scientists and oncologists in more than 300 hospitals in over 30 countries. It encompasses all aspects of cancer research, from translational research and new drug development to large phase III clinical trials and meta-analyses.

The 170 members of the EORTC Headquarters staff handle some 6,000 new patients enrolled each year in cancer clinical trials, approximately 30 protocols that are permanently open to patient entry, over 50,000 patients who are in follow-up, and a database of more than 180,000 patients.

The ultimate goal of the EORTC is to improve the future of cancer therapy by developing new agents and innovative approaches and to test more effective treatment strategies using commercially available drugs, or surgery and radiotherapy.

1. Llovet, J.M. et al (2012) EASL-EORTC Clinical Practice Guidelines: Management of Hepatocellular Carcinoma. Available at

2. Aflatoxins are naturally occurring toxins produced by many species of the fungus Aspergillus and are among the most carcinogenic substances known. Dietary exposure to aflatoxin B1, derived from the fungi Aspergillus flavus and Aspergillus parasiticus, is an important co-factor for HCC development in parts of Africa and Asia. These moulds are ubiquitous in nature and contaminate a number of staple foodstuffs in tropical and subtropical regions.

3. Downstaging is a situation in which a patient with a previously unresectable tumour or large number of tumours becomes eligible for surgery (resection) or transplant after treatment.