Saturday, April 27, 2013

Hepatitis C: Closing in on its viral origins

Hepatitis C: Closing in on its viral origins

26 April 2013 Last updated at 21:17 ET

Artwork of HCV

The virus behind Hepatitis C has been the target of virologists, epidemiologists and geneticists for years, in a bid to find out the animal host from which it likely came. But Prof Jonathan Ball, a virologist at the University of Nottingham, UK, says early indications that bats are the culprit may yet be proven wrong.

The omnipresent bat represents around one fifth of mammal species, yet remains strangely enigmatic.

Known to be the source of a range of human viral infections such as Sars and ebola, a recent study published in PNAS suggests that bats are a large natural reservoir to groups of viruses similar to the hepatitis C virus (HCV).

HCV is a life-threatening infection affecting more than 150 million people worldwide and its origin has eluded scientists for years.

To define if bats were a possible source for HCV-like viruses, Phenix-Lan Quan from Columbia University in New York and her colleagues analysed the blood from hundreds of bats living in South America, Africa and Asia.

To expose any infectious payload that the bats carried, the team used a method called high-throughput sequencing, which surveys all of the genetic material - nucleic acids - present in their blood.

In amongst the bat DNA, in approximately 5% of the animals tested, they discovered novel genetic sequences that were similar to nucleic acid present in viruses belonging to two groups - or genera - called pegiviruses and hepaciviruses. HCV is a member of the hepacivirus genus.

“Start Quote
My prediction is that we will find a range of bat and/or rodent species to be infected with viruses that represent the immediate source of human infections in those parts of Africa and South Asia where HCV seems to have originated”
Quote Prof Peter Simmonds University of Edinburgh

To determine the evolutionary history and relatedness of these viruses, they performed computer analyses to build what is called a phylogenetic tree.

Unlike a family tree, which is built using archive records of significant events like births, deaths and marriages, phylogenetic trees use the historic record written into the sequence of information stored in nucleic acids.

During replication, virus genetic material changes, or mutates, and these mutations accumulate over time allowing the virus to evolve.

Determining the number of genetic differences that exist between viruses gives an idea of how related they are - the fewer the changes, the more closely related - and phylogenetic trees represent this genetic relationship.

Viruses located on connecting branches are most related and the shorter the branches, the more related they are.

In the pegivirus and hepacivirus tree constructed by Dr Quan, the branches leading to clusters of bat virus sequences were numerous and long, indicating that bats have long been infected by a great variety of strains; more so than humans.

The branching pattern of the phylogenetic tree can also provide a clue to the origins of HCV.

If bats are the source of this virus, then the HCV sequences should nestle amongst the branches of the bat hepaciviruses - and at first sight they do.

But before we designate the much-maligned bat as public enemy number one, is there sufficient evidence to suggest that these vital pollinators and insect predators are the direct source of deadly HCV?

Equine enigma

Scientists have used phylogenetic trees to identify the source of many viral infections.

Beccari's freetail batA 2005 paper in Science showed that Sars passed from bats to civet cats then on to humans, and a 2010 Royal Society journal article reported that HIV arose following transmission from African primates.
Initial studies suggested that the bat was responsible, but other suspects have now entered the line-up

The evidence supporting these particular animal-human transmissions - or zoonoses - is strong.

For example, in trees of virus sequences derived from extensive sampling of wild primate and monkey species, HIV is embedded firmly on the branch of the tree containing chimpanzee viruses. Genetically, HIV is most closely related to its chimpanzee counterparts and they are the most likely source.

In the hepacivirus tree, research in Emerging Infections Diseases has shown that HCV is more related to viruses found in horses and dogs than it is to those present in bats, but the branch leading to HCV is very long - it contains lots of genetic change and therefore long evolutionary timeframe.

A virus could have made the jump into humans millennia ago, but this unlikely.

The key to it all is in the virus sampling.

Just as an identity parade is only useful if the guilty party is present, phylogenetic analysis can only identify the cause of a virus outbreak if the most probable source is included.

Although Dr Quan's analysis includes far more viral sequences than has been possible before, the hepacivirus and pegivirus line-up still contained very few suspects.

"Our findings shed new light on the deep evolutionary history of those viruses that ultimately resulted in HCV," Dr Quan explained.

"We show that all known hepaciviruses and pegiviruses - including primates, horses and dogs - fall within the phylogenetic diversity of the bat-derived viruses, suggesting a longer evolutionary history of these viruses in bats than in primates, horses or dogs."

Whilst Dr Quan believes that bats harbour the greatest array of these important viruses, she stops short of arguing that her data prove that bats are the source of HCV.

"With our current data, we cannot conclude whether or not bats are the 'ultimate' reservoir of hepaciviruses and pegiviruses, nor whether HCV came from bats," she said. "To be truly able to answer this question, you would need to study a far larger sample of potential reservoir hosts."

Of mice and men

And to prove this point, a related study published in the journal mBio by a team led by Prof Amit Kapoor, also from Columbia University in New York, reported that numerous species of rodents also harbour hepacivirus and pegiviruses.

Rat and her youngJust like the bat viruses, these too exhibited a large degree of genetic variability, hinting at an enduring history of infection.
Future studies could see rodents emerge as the confirmed source of the virus

None of the rodent sequences was more related to HCV than the horse hepaciviruses, but one of the co-authors of this study, Prof Peter Simmonds from the University of Edinburgh, thinks that the large degree of variability observed in these rodent viruses might prove significant.

"It seems as though different bat and rodent species carry a remarkably diverse range of HCV-like viruses," he said.

"None of these are very close genetically to HCV, but with such limited sampling, it certainly remains possible that other variants exist in other species that match HCV more closely."

Although leaving open the possibility that other animals might be the source of HCV, he added: "My prediction is that we will find a range of bat and/or rodent species to be infected with viruses that represent the immediate source of human infections in those parts of Africa and South Asia where HCV seems to have originated. It's difficult to know what those species are, when and how such species jumps occurred."

So, despite recent growth spurts, the hepacivirus and pegivirus phylogeny is still more of a sapling than a fully grown tree.

Extensive virus sampling from global mammalian species will add further branches and bring us closer to understanding the origin of HCV.

Bats and rodents have been around for more than 50 million years, so it's no surprise they've picked up one or two viruses in their travels.

Some of these, driven by habitat encroachment and human activity, have undeniably passed into humans.

But whether HCV arose from bats or rodents remains to be seen.

Related Internet links
Jonathan Ball at University of Nottingham

The BBC is not responsible for the content of external Internet sites

Related Stories

Updated: May 4 2014
To include this link: Yellow Blood: Hepatitis C and the Modernist Settlement in Japan.
In 1964, HCV infection via direct blood-to-blood contact with contaminated blood was happening wherever medicine could afford transfusion technology and wherever blood products and hypodermic syringes were in use as therapies or therapy delivery systems. Although the hepatitis C virus probably originated in West Africa in the late 15th century, its global sweep and pandemic status in the world today are both intimately linked with progression of the modernist settlement: the dualistic epistemological structure of modernity in which science and technology are divided from and purified of culture and politics.

Friday, April 26, 2013

EASL: Anemia Top Side Effect of HCV Antivirals

Anemia Top Side Effect of HCV Antivirals

By John Gever, Deputy Managing Editor, MedPage Today

Published: April 26, 2013
Reviewed by Zalman S. Agus, MD; Emeritus Professor,
Perelman School of Medicine at the University of Pennsylvania

 Action Points

Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
This is a preliminary analysis of the North American experience with boceprevir and telaprevir in the treatment of HCV, predominantly genotype 1, across a broad spectrum of clinical practices in a cohort enriched with African-American patients and cirrhosis.
Major adverse events were anemia and rash. Patients taking telaprevir had SVR12 of 91% to 96%, and for boceprevir patients it ranged from 63% to 87%.

AMSTERDAM -- Two years after direct-acting antiviral drugs for hepatitis C virus (HCV) infection hit the U.S. market, anemia has been far and away their most significant adverse effect, researchers said here.

Outcomes in more than 1,400 U.S. patients taking a HCV protease inhibitor in routine practice for chronic infection indicated that more than half had experienced anemia, whether they received boceprevir (Victrelis) or telaprevir (Incivek), according to Michael W. Fried, MD, of the University of North Carolina in Chapel Hill.

Triple therapy with one of these drugs plus ribavirin and pegylated interferon is now the standard of care for HCV genotype 1.

Although severe skin rashes have been telaprevir's most talked-about side effect, prompting the FDA to add a boxed warning to the drug's label, severe anemia was much more common. Of the 1,082 patients in the study taking telaprevir, 27 showed severe anemia, compared with five patients developing severe rash, Fried and colleagues found.

Among 344 patients on boceprevir, six developed severe anemia.

These data were collected by a consortium of 44 academic centers and 59 community-based clinics in the U.S., which have sought to enroll all patients receiving these drugs. The only exclusion criteria were consent refusal or participation in another study of HCV therapies.

Beyond that, clinicians were free to prescribe dosing regimens and manage adverse effects according to their own judgment.

Anemia in most patients was treated mainly by reducing ribavirin dosages, for patients with cirrhosis as well as those without (65% and 54%, respectively).

Clinicians resorted to erythropoietin-type drugs in 13% of cirrhotic patients and 19% of those with no cirrhosis. Transfusions were given to 17% and 8% of cirrhotic and noncirrhotic patients, respectively.

Baseline cirrhosis was a significant risk factor for severe anemia and premature discontinuation of treatment. Fried and colleagues found odds ratios of 1.5 to 2.2 (all P<0.05) for risk of these outcomes as well as for any serious adverse event and for early discontinuation attributed to adverse effects.

Some 11% of the 550 patients with cirrhosis developed decompensation on treatment, compared with 1% of noncirrhotic patients.

Fried and colleagues also found virologic response rates in their patients to be similar to, if not better than, those seen during the drugs' clinical trials.

Patients taking telaprevir had HCV viral loads below the limits of detection or quantitation at rates of 91% to 96% at treatment week 12, depending on prior treatment history.

Corresponding data for boceprevir patients ranged from 63% to 87%.

About one-quarter of patients in the study stopped all therapy prematurely. Lack of efficacy and adverse events accounted for 35% and 40% of discontinuations, respectively.

At a press briefing, Laurent Castera, MD, of Centre Hospitalier Universitaire de Bordeaux in France, who was not involved with the study, said it was noteworthy in representing a real-world patient population, as opposed to the carefully selected samples enrolled in clinical trials.

Despite the broader mix of patients seen in the post-marketing study, Castera said the efficacy results were "comparable" to those seen in the two drugs' registration trials. Rates of anemia and other adverse events also tracked closely with previous trial results, in which some degree of anemia occurred with both drugs in half of patients.

The study was funded by Vertex, Merck, Kadmon, and Genentech.

Fried reported relationships with Genentech, Merck, Vertex, Gilead, Bristol-Myers Squibb, and Abbott.

Castera reported relationships with Bristol-Myers Squibb, Merck, Gilead, and Echosens.

Primary source: European Association for the Study of the Liver
Source reference:
Fried M, et al "HCV-TARGET: a longitudinal, observational study of North American patients with chronic hepatitis C (HCV) treated with boceprevir or telaprevir" EASL 2013; Abstract 818.

Add Your Knowledge ™

John Gever
Senior Editor

John Gever, Senior Editor, has covered biomedicine and medical technology for 30 years. He holds a B.S. from the University of Michigan and an M.S. from Boston University. Now based in Pittsburgh, he is the daily assignment editor for MedPage Today as well as general factotum on the reporting side. Go Pirates/Penguins/Steelers!

Related - Hep C Drug Linked to Fatal Skin Reactions

EASL Coverage @ MedPage Today
Obesity Plus Drinking Worst Combo for Liver4/26/2013
AMSTERDAM -- Obesity and heavy drinking are each known risk factors for liver disease, but together they appear to be even worse, researchers said here. more

AMSTERDAM -- An investigational protease inhibitor led to viral cures in about four out of five hepatitis C virus (HCV) patients, a researcher reported here.  more
AMSTERDAM -- Treatment-naive patients with hepatitis C virus infection showed high viral cure rates when treated with simeprevir, a once-daily oral drug, along with standard therapy, researchers said here. more
AMSTERDAM -- An "optimal regimen” of three anti-hepatitis C drugs and a general antiviral medication yielded high and sustained response rates in difficult-to-treat patients, a researcher said here. more
AMSTERDAM -- Hitting hepatitis C virus from three directions was a winner in a phase II trial involving patients with the particularly hard-to-treat viral genotype 1a, researchers said here. more

New Drug Stimulates Immune System to Kill Infected Cells in Animal Model of Hepatitis B Infection

Apr. 26, 2013 — A novel drug developed by Gilead Sciences and tested in an animal model at the Texas Biomedical Research Institute in San Antonio suppresses hepatitis B virus infection by stimulating the immune system and inducing loss of infected cells.

In a study conducted at Texas Biomed's Southwest National Primate Research Center, researchers found that the immune modulator GS-9620, which targets a receptor on immune cells, reduced both the virus levels and the number of infected liver cells in chimpanzees chronically infected with hepatitis B virus (HBV). Chimpanzees are the only species other than humans that can be infected by HBV. Therefore, the results from this study were critical in moving the drug forward to human clinical trials which are now in progress.

The new report, co-authored by scientists from Texas Biomed and Gilead Sciences, appears in the May issue of Gastroenterology. Gilead researchers had previously demonstrated that the same therapy could induce a cure of hepatitis infection in woodchucks that were chronically infected with a virus similar to human HBV.

"This is an important proof-of-concept study demonstrating that the therapy stimulates the immune system to suppress the virus and eliminate infected liver cells," said co-author Robert E. Lanford, Ph.D., of Texas Biomed. "One of the key observations was that the therapy continued to suppress virus levels for months after therapy was stopped.

The current therapy for HBV infection targets the virus and works very well at suppressing viral replication and delaying progression of liver disease, but it is a lifelong therapy that does not provide a cure.

"This GS-9620 therapy represents the first conceptually new treatment for HBV in more than a decade, and combining it with the existing antiviral therapy could be transformative in dealing with this disease," stated Lanford.

The Gilead drug binds a receptor called Toll-Like Receptor 7 that is present in immune cells. The receptor normally recognizes invading viruses and triggers the immune system to suppress viral replication by the innate immune response and kill infected cells by the adaptive immune response, thus orchestrating both arms of the immune system.

HBV damages the liver, leading to cirrhosis and liver cancer. Liver cancer is the fifth most common cancer worldwide and the third most common cause of cancer death. According to the United States Centers for Disease Control and Prevention (CDC), up to 1.4 million Americans are chronically infected with HBV.

The World Health Organization estimates that two billion people have been infected with the hepatitis B virus, resulting in more than 240 million people with chronic infections and 620,000 deaths every year.

Story Source:
The above story is reprinted from materials provided by Texas Biomedical Research Institute, via EurekAlert!, a service of AAAS.
Note: Materials may be edited for content and length. For further information, please contact the source cited above.

Journal Reference:
  1. Robert E. Lanford, Bernadette Guerra, Deborah Chavez, Luis Giavedoni, Vida L. Hodara, Kathleen M. Brasky, Abigail Fosdick, Christian R. Frey, Jim Zheng, Grushenka Wolfgang, Randall L. Halcomb, Daniel B. Tumas. GS-9620, an Oral Agonist of Toll-Like Receptor-7, Induces Prolonged Suppression of Hepatitis B Virus in Chronically Infected Chimpanzees. Gastroenterology, 2013; DOI: 10.1053/j.gastro.2013.02.003


Source - ILC Press

Related - EASL: New Studies Prove Lethal Link between Alcohol, Weight and Liver Disease in Women

Also View -
Feb 20 2013- EASL-Burden of Liver Disease in Europe: Looks at leading causes of cirrhosis and primary liver cancer in Europe


Source - ILC Press

Also View - EASL: New Advances in The Management of Patients with Cirrhosis

EASL 2013- Watch: HCC, NAFLD and NASH

Source - ILC Press

EASL - Novel screening tests for liver cancer

Novel screening tests for liver cancer

Amsterdam, The Netherlands, Friday 26 April 2013: New data from two clinical trials presented today at the International Liver Congress™ 2013 demonstrate substantial improvements in the detection of both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) using diagnostic urine tests.

HCC is common throughout the world and most often develops as a late complication of chronic viral hepatitis or cirrhosis of any cause. The overall survival rate of HCC is poor and so screening for HCC offers the best hope for early detection, eligibility for treatment, and improved survival. While effective therapies exist, the available screening tests to detect HCC – alpha-fetoprotein (AFP) and ultrasound – are reported to have low sensitivity and specificity (50–85% and 70–90%, respectively).

Preliminary data demonstrate the performance of urinary metabolites in helping to diagnose HCC. Urine samples were collected from four subject groups in West Africa on the case-control platform of PROLIFICA 'Prevention of Liver Fibrosis and Carcinoma in Africa' as follows: patients with HCC (n=65), cirrhosis (Cir, n=36), non-cirrhotic liver disease (DC, n=110) and healthy controls (NC, n=91). HCC patients were diagnosed using EASL guidelines.

Multivariate analyses of urinary nuclear magnetic resonance (NMR) spectra showed a distinct profile for urine of patients with HCC compared to Cir, DC and NC with sensitivity of 87%, 86% and 97% respectively. These results suggest that Urinary metabolite profile outperforms serum AFP which only differentiated HCC from these groups by 79% (Cir), 75% (DC) and 76% NC) respectively. The metabolites that were significantly increased (p< 0.001) in HCC patients compared to all groups of control were methionine, acetylcarnitine, carnitine, N-acetylglutamate, 2-oxoglutarate, indole-3-acetate, and creatine; whereas creatinine was significantly lower in HCC than controls.

EASL General Secretary, Prof. Mark Thursz commented: "These findings will be welcomed by physicians as they validate urinary metabolic profiling as a potential screening tool for HCC, with superior diagnostic accuracy to serum AFP and – if investigated further and put into practice – this non-invasive technique could simplify and improve clinical diagnosis and outcomes for patients."
Similarly, detection of CC remains a diagnostic challenge and physicians will be encouraged by results from a Phase II study showing that a combined bile and urine proteomic test increased diagnostic accuracy of CC in patients with biliary strictures (an abnormal narrowing of the common bile duct) of unknown origin.

Having recently established diagnostic peptide marker models in bile and urine to detect both local and systemic changes during CC progression, investigators combined both models with the aim of reaching a higher diagnostic accuracy.

The data demonstrated this model enables impressive CC-diagnosis with an accuracy of more than 90% that is most applicable for patients with biliary strictures of unknown origin referred to endoscopy.    Prof. Mark Thursz added: "These important findings substantially improve the diagnosis of CC and may lead to early therapy and improved prognosis. Overall both data sets demonstrate the increasing value of proteomic and metabonomic techniques and if confirmed by further investigation, clinicians may soon be using simple urine dip-stick tests to diagnose HCC and CC."

A logistic regression model composed of the bile and urine proteomic classification factors lead to an area under curve (AUC) of 0.96, and 92% sensitivity and 84% specificity at the best cut-off. Only three of the 36 CC patients were false negative and two of the 33 PSC patients were false positive classified. Inclusion of CA19-9 and bilirubin values to the logistic regression model was of minor benefit.

Cholangiocarcinoma or bile duct cancer is rare and almost always adenocarcinoma which starts in the lining of the bile duct. The cause of most cholangiocarcinomas is unknown but people with chronic inflammatory bowel conditions or congential abnormalities of the bile duct have a higher risk of developing the cancer.

Disclaimer: the data referenced in this release is based on the submitted abstract. More recent data may be presented at the International Liver Congress™ 2013.
Notes to Editors

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:
  • The International Liver CongressTM which is the main scientific and professional event in hepatology worldwide
  • Meetings including Monothematic and Special conferences, Post Graduate courses and other endorsed meetings that take place throughout the year
  • Clinical and Basic Schools of Hepatology, a series of events covering different aspects in the field of hepatology
  • Journal of Hepatology published monthly
  • Participation in a number of policy initiatives at European level
About The International Liver Congress™ 2013
The International Liver Congress™ 2013, the 48th annual meeting of the European Association for the study of the Liver, is being held at the RAI Convention Centre in Amsterdam from April 24 – 28, 2013. The congress annually attracts in excess of 9000 clinicians and scientists from around the world and provides an opportunity to hear the latest research, perspectives and treatments of liver disease from principal experts in the field.

1 De Masi S et al, Screening for hepatocellular carcinoma. Digestive and Liver Disease 2005;3(4): 219 300. 2 Ladep NG et al, URINARY METABOLIC PROFILE DISCRIMINATES HEPATOCELLULAR CARCINOMA BETTER THAN SERUM ALPHA FETOPROTEIN IN WEST AFRICANS. Presented at the International Liver Congress™ 2013 3 EASL Guidelines: Management of Hepatocellular Carcinoma. Available at [Accessed 11/4/13] 4 Metzger J, et al, A COMBINED BILE AND URINE PROTEOMIC TEST INCREASES DIAGNOSTIC ACCURACY OF CHOLANGIOCARCINOMA IN PATIENTS WITH BILIARY STRICTURES OF UNKNOWN ORIGIN. Presented at the International Liver Congress™ 2013 5 Macmillan Cancer Support. Bile duct cancer (cholangiocarcinoma). Available at [Accessed 9/4/13]

EASL - Interferon-free, triple-DAA regimen safe, effective for chronic HCV

HealioHepatologyChronic HepatitisNews

Interferon-free, triple-DAA regimen safe, effective for chronic HCV
April 26, 2013

Nearly all patients with chronic hepatitis C treated with an interferon-free drug regimen for 12 or 24 weeks experienced sustained virologic response in a study presented at the International Liver Congress in Amsterdam.

Researchers administered 100-200 mg HCV protease inhibitor ABT-450 (AbbVie) with 100 mg ritonavir (ABT-450/r) once daily to patients with chronic hepatitis C genotype 1, along with 25 mg NS5A inhibitor ABT-267 once daily and 400 mg non-nucleoside NS5B inhibitor ABT-333 twice a day, and weight-based ribavirin, for 12 or 24 weeks. The cohort included 79 12-week and 80 24-week recipients among treatment-naive patients, and 45 12-week and 43 24-week recipients among previous nonresponders. Patients were either treatment-naive or nonresponsive to prior pegylated interferon/ribavirin therapy.

Sustained virologic response (SVR) rates at 4 weeks among treatment-naive participants were 98.7% in the 12-week and 96.2% in the 24-week group. Among prior nonresponders, SVR4 rates were 93.3% in the 12-week and 97.7% in the 24-week groups.

Among treatment-naive patients, SVR12 was 99% in the 12-week and 93% in the 24-week group, while nonresponders experienced SVR12 in 93% of 12-week and 98% of 24-week cases. SVR24 was achieved by 96% of 12-week and 90% of 24-week treatment-naive participants and 93% of 12-week and 95% of 24-week nonresponders. Across the cohort, SVR was similar regardless of IL28B genotype, baseline HCV RNA levels, fibrosis stage and infection with HCV genotype 1a compared with 1b.

Commonly reported events included headache, fatigue, insomnia, diarrhea and nausea. Four patients withdrew from the study after experiencing serious adverse events.

“The consistency of high sustained viral response rates that we have seen in clinical trials across populations is encouraging, especially given the proportion of patients with these characteristics who have failed with interferon plus ribavirin treatment,” researcher KrisV. Kowdley, MD, director of research at the Digestive Disease Institute at Virginia Mason Medical Center in Seattle, said in a press release.

Phase 3 trials are under way for the 12-week regimen.

For more information:

Kowdley KV. #3: Safety and Efficacy of Interferon-Free Regimens of ABT-450/R, ABT-267, ABT333 ± Ribavirin in Patients With Chronic HCV GT1 Infection: Results From the Aviator Study. Presented at: The International Liver Congress 2013; April 24-28, Amsterdam

Meeting News Coverage