Scientists make breakthrough in study on bile duct cancer with discovery of new gene mutations

Bile duct cancer is a deadly type of liver cancer with a poor prognosis. The latest breakthrough could help scientists learn more about the disease, and potentially pave the way for improved treatments. Image: Raycat/iStockphoto

• Asian researchers report the first comprehensive genomic study of Bile Duct Cancer, a deadly type of liver cancer caused by liver fluke infection
• Liver flukes, which are food-borne parasites, are thought to infect over 6 million people in Thailand
• Joint Singapore-Thai team uncovers new critical genes responsible for the onset of Bile Duct Cancer.

Singapore, 7 May 2012 - A combined team of scientists from Singapore and Thailand has made a significant breakthrough in understanding the cause of bile duct cancer, a deadly type of liver cancer. Using the latest genomic technologies, the researchers identified several new genes frequently mutated in bile duct cancers, paving the way for better understanding on how bile duct cancers develop.

The Singapore-Thailand team was led by Professor Teh Bin Tean, Associate Professor Patrick Tan, Associate Professor Steve Rozen (Duke-NUS Graduate Medical School of Singapore) and Professor Vajarabhongsa Bhudhisawasdi from Thailand’s Khon Kaen University. The breakthrough came after two years of intensive research, which saw scientists from Singapore visiting the villagers in northern Thailand, and Thai researchers coming to Singapore to work in NCCS laboratories. The discovery was published online on 6 May 2012 in Nature Genetics.

Bile Duct Cancer, or Cholangiocarcinoma, is a fatal cancer with poor prognosis. Accounting for 10 to 25 per cent of all primary liver cancers worldwide, bile duct cancer is a prevalent disease in Southeast Asia, particularly in the Northeast of Thailand which sees about 20,000 new cases each year. The high incidence in Thailand is attributed to long-term consumption of raw fish that is infected with liver flukes, which are food-borne parasites found in fish. Liver fluke infections are widespread in Northeast Thailand, where they are thought to occur in over 6 million people. Once eaten, the flukes accumulate in the bile ducts of the human host, causing constant infection and the onset of cancer.

Professor Teh, who was a recipient of the Singapore Translational Research (STaR) Investigator Award in 2009 and the Director and Principal Investigator of the NCCS-VARI Translational Cancer Research Laboratory at the National Cancer Centre Singapore, said the study will pave the way for a better understanding of the roles that newly identified genes play in the development of bile duct cancer. "This discovery adds depth to what we currently know about bile duct cancer. More important is that we are now aware of new genes and their effects on bile duct cancer and we now need to further examine their biological aspects to determine how they bring about the onset of Cholangiocarcinoma."

Using state of the art DNA sequencing platforms, the researchers analysed eight bile duct cancers and normal tissues from Thai patients, and discovered mutations in 187 genes. The team then selected 15 genes that were frequently mutated for further analysis in an additional 46 cases. Many of these genes, such as MLL3, ROBO2 and GNAS, have not been previously implicated in bile duct cancers.

"With this finding we now know much more about the molecular mechanisms of the disease and we can draw up additional measures that can be taken while we identify the most appropriate treatment protocols. We are talking about the potential to save many lives in Thailand," said Professor Vajarabhongsa Bhudhisawasdi, Director of the Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University of Thailand. "Also, this study shows that we can work closely with our counterparts in other countries and share our expertise and experience to improve the lot for the people."

The researchers also compared the bile duct cancers to other related cancers of the liver and pancreas. Surprisingly, they found that the bile ducts cancers shared certain similarities with pancreatic cancer. "This research provides a strong direction for future studies," said Associate Professor Patrick Tan, faculty member of the Cancer and Stem Cell Biology Programme at Duke-NUS. "Cholangiocarcinoma and Pancreatic Duct Adenocarcinoma appear to share more molecular similarities than earlier studies had indicated, and suggest that there are common biological pathways between the two cancers. By studying these pathways, we can then shed more light on how these tumours develop."

Dr Chutima Subimerb, a Thai scientist involved in the project, said she was pleased with the collaboration and to be able to participate in this health diplomacy project. "We are very privileged to be able to work alongside Prof Teh and the other scientists from Singapore. By pooling our resources we were able to make this discovery which will have very wide impact on the people, especially the poor people who have been eating the fish that they catch from the ponds and rivers in the region. I believe this is only a first step and we will see even more collaborations in time to come between our two countries in the field of scientific research."

The research was funded by the Ministry of Health’s National Medical Research Council, Millennium Foundation, Lee Foundation, National Cancer Centre Research Fund, Duke-NUS Graduate Medical School Singapore, Cancer Science Institute Singapore, Research Team Strengthening Grant, National Genetic Engineering and Biotechnology Center and the National Science and Technology Development Agency (Thailand).

About NCCS

The National Cancer Centre Singapore (NCCS) is the cancer centre dedicated to providing a holistic and multidisciplinary approach to cancer treatment and patient care. We treat almost 70 per cent of the public sector oncology cases. Through the sub-specialisation of its oncology, patients can receive the best in treatment and care. NCCS is engaged in cutting-edge clinical and translational research which has received several international acclaims. The national centre is accredited by the Joint Commission International in 2010 for quality patient care and safety. NCCS, which is set to be a global leading institution, also offers specialist training programmes to other medical institutions here and overseas.

About Duke-NUS Graduate Medical School Singapore

The Duke-NUS Graduate Medical School Singapore (Duke-NUS) was established in 2005 as a strategic collaboration between the Duke University School of Medicine, located in N.Carolina, USA and the National University of Singapore (NUS). Duke-NUS offers a graduate entry, 4-year M.D. (Doctor of Medicine) training program based on the unique Duke model of education, with one year dedicated to independent study and research projects of a basic science or clinical nature. Duke-NUS also offers M.D/PhD and PhD programs. As a player in Singapore’s biomedical community, Duke-NUS has identified five Signature Research Programs: Cancer & Stem Cell Biology, Neuroscience and Behavioral Disorders, Emerging Infectious Diseases, Cardiovascular & Metabolic Disorders, and Health Services and Systems Research. For more information, please visit www.duke-nus.edu.sg.

About Khon Kaen University of Thailand

Khon Kaen University (KKU) was one of four regional universities established in 1964 as part of a decentralized development plan for higher education in Thailand. The campus is located in the Northwestern sector of Khon Kaen, just a few kilometers from the center of the city. Situated in a most attractive park, the campus covers approximately 900 hectares. From small beginnings, KKU has grown enormously and is today home to eighteen faculties, three colleges, 7 academic support centers, a hospital, a research institute and 22 research excellent centers. In addition several new institutes are currently in pipeline and will, in time, open the University's door further to the public and increase its roles, responsibilities and commitments to the region around. Currently the number of students is approximately 40,000 (including 9,800 postgraduates and about 290 students from overseas).

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Biolex Sells LEX System to Synthon and Initiates Sale of Locteron(R)

PRESS RELEASE

May 7, 2012, 9:03 a.m. EDT

PITTSBORO, NC, May 07, 2012 (MARKETWIRE via COMTEX) -- Biolex Therapeutics, Inc. announced that it has sold its LEX System, a proprietary platform for the development and production of biologics, to Synthon, a Netherlands-based specialty pharmaceutical company. Also included in the sale were two preclinical product candidates uniquely enabled by the LEX System: BLX-301, a humanized and glyco-optimized anti-CD20 antibody for the treatment of non-Hodgkin's B-cell lymphoma and other B-cell malignancies; and BLX-155, a direct-acting thrombolytic designed to dissolve blood clots in patients. Financial terms of the sale will not be disclosed.

Locteron Sale Biolex also announces that it has initiated the sale of its remaining Phase-3 ready asset, Locteron(R) controlled-release interferon for the treatment of HCV and HBV.

Locteron, controlled-release interferon alpha 2b, is designed to offer key advantages compared to currently approved interferon products. In Phase 2b clinical trials in hepatitis C (HCV) Locteron demonstrated statistically significant reductions in flu-like symptoms, reduced rates of depression, and cutting in half the number of injections required compared to pegylated interferon. It is estimated that current worldwide sales of interferon are approximately $2.5 billion. Flu-like symptoms and depression are the two most important side effects of interferon and limit treatment adherence.

Locteron incorporates an advanced controlled-release drug delivery technology that allows dosing once every two weeks. This is considerably more convenient than the currently approved interferon products, Pegasys(R) and PEG-Intron(R), each of which are immediate release and require dosing every week. More importantly, Locteron's controlled-release mechanism results in the gradual release of interferon alpha 2b to patients over the duration of two weeks and avoids the early peak plasma levels of the active interferon that characterize the pegylated interferons. This controlled-release mechanism is designed to reduce the frequency and severity of flu-like symptoms and depression commonly experienced by patients treated with pegylated interferons.

"We believe that even if all-oral interferon-free regimens are eventually approved, a Locteron-containing regimen will achieve at least equal efficacy (SVR rate), but likely with a shorter duration of treatment that is well tolerated by patients. A regimen with Locteron will be much more cost-effective, and in a payer driven world, that means it will be preferentially reimbursed," said Jan Turek, President and Chief Executive Officer of Biolex. "Many countries may require the use of a more cost-effective interferon-containing regimen as first-line therapy before reimbursing a more expensive interferon-free combination. There are already signs of this dynamic as several cost-effectiveness studies have recently been published that claim that using direct-acting anti-viral agents is not cost-effective for patients with a specific host genotype who are very interferon responsive. Beyond HCV, HBV is a smaller, albeit solid and growing opportunity for Locteron, as an interferon-based treatment in HBV can effectively provide a 'cure' by sero-conversion of the patient, a preferred outcome as opposed to the current chronic, life-long therapy keep HBV suppressed."

Locteron has strong patent protection through 2028, and has worldwide freedom to operate (FTO). Biolex intends to sell the worldwide development and commercialization rights to Locteron.

Locteron is an investigational therapeutic candidate and has not been approved for sale by the United States Food and Drug Administration or by any international regulatory agency.

About Biolex Therapeutics Biolex is a privately held biopharmaceutical company that developed the patented LEX System to manufacture follow-on biologics, hard-to-make therapeutic proteins and optimized monoclonal antibodies. The LEX System is a novel technology that genetically transforms the aquatic plant Lemna to enable the production of biologic product candidates. The company's product candidates were designed to provide best-in-class efficacy/tolerability profiles while incorporating proven mechanisms of action. Biolex's lead product candidate, Locteron, has completed five clinical trials, including two Phase 2b clinical trials for the treatment of chronic hepatitis C

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Will we ever have an HIV vaccine?

Image by Dr. A. Harrison; Dr. P. Feorino

May 7th, 2012 by Ed Yong

For around 30 years we have lived under the spectre of HIV. In the early 1980s, the mysterious appearance of symptoms that would later be known as AIDS led to unprecedented efforts to unmask the cause. On 23 April 1984, Margaret Heckler, the US Secretary of Health and Human Services, told the world that scientists had identified the virus that was the probable cause of AIDS. She was correct. She also said that a vaccine would be “ready for testing in approximately two years.” She was wrong.

Despite 28 years of research, there is still no vaccine that provides effective protection against HIV, and in that time around 25 million people have died of HIV-related causes. To understand why creating a vaccine is so hard, you need to understand HIV. This is no ordinary virus. Scientists who study it speak of it with a mix of weary frustration and awed reverence.

The virus is the most diverse we know of. It mutates so rapidly that people might carry millions of different versions of it, just months after becoming infected. HIV’s constantly changing form makes it unlike any viral foe we have tried to thwart with a vaccine. “Almost every vaccine that’s been developed protects against a small number of strains,” says Gary Nabel, Director of the Vaccine Research Center at the US National Institute of Allergy and Infectious Diseases (NIAID).

Vaccines train the immune system to recognise part of a virus, creating a long-term armada of antibodies that seek and destroy the invader, should it ever show its face. For HIV, the most obvious target is gp120, the surface protein that it uses to attach itself to human cells. But gp120 also constantly changes shape, making it difficult to recognise. It also comes in clusters of three that are shielded by bulky sugar molecules, hiding it from the immune system.

On top of that, HIV targets immune cells, the very agents that are meant to kill it. And it can hide for years by shoving its DNA into that of its host, creating a long-term reservoir of potential infection.

So, creating an HIV vaccine is like trying to fire a gun at millions of shielded, moving targets. Oh, and they can eat your bullets.

Uphill struggle

So far, nature has provided little reassurance that a vaccine against HIV is even possible. For virtually every other microbe, there are people who naturally recover from their infections. “Nature itself provides the proof-of-concept experiment. It has told you that the body can inherently do this,” says Anthony Fauci, an immunologist who heads NIAID. But when it comes to HIV, “we have the astounding reality that, with more than 30 million people living with the virus, there is not a single documented case of someone mounting an immune response to completely eliminate the virus from their body.” Some people have the right genetic qualities to keep the virus in check, but no one clears it.

Given these challenges, it should be no surprise that vaccine research has been, to quote one researcher, a “Sisyphean onslaught of disappointments”. Only three potential candidates have made it through clinical trials. Vaxgen’s AIDSVAX vaccine, consisting of two fragments of the gp120, failed to provide any protection. Merck’s v520 vaccine, consisting of a harmless cold virus carrying three HIV genes, fared even worse. It was meant to marshall immune cells called T-cells to kill off infected cells. It failed. Worse still, the trial had to be stopped early because vaccinated people seemed to be more susceptible to infections, for reasons we still do not fully understand.

The only sliver of success came in 2009. A Thai trial of more than 16,000 people – the largest one yet – had been testing a combination of two vaccines: a bird virus containing three HIV genes, which was meant to prime the immune system, and a tweaked version of the AIDSVAX vaccine to act as a booster. Since both vaccines had failed individually, critics argued that the trial was a waste of time and money. But to many people’s surprise, the combination reduced the risk of infection by 31% – a statistically significant effect, though too low for a useable vaccine. (For comparison, the measles and polio vaccines are around 95% effective).

Some scientists were sceptical about the results, noting that the protection was short-lived and confined to people at low risk of infection. Others saw a ray of hope after years of frustration, a sign that a vaccine is in principle possible. Either way, the trial was confusing, especially since the vaccines did not reduce the levels of virus in infected people. Scientists are still trying to work out why the vaccine had any effect at all.

Renewed hope

But despite the muted results from existing trials, scientists in the field are unfazed. The reason, according to Wayne Koff from the International AIDS Vaccine Initiative, is that since the Thai results were announced, “the field that has begun to undergo a renaissance.”

It turns out that many HIV patients carry secret weapons – “broadly neutralising antibodies” – that can attack a wide range of HIV viruses. For these patients, it is too late. Their infections are already in full swing and the virus can mutate around their defences. But the discovery proved that HIV’s vaunted diversity is not the roadblock for vaccines that many scientists feared. If we taught the immune system to make these antibodies early, we could destroy the virus before it gained a foothold.

It is possible to isolate the right antibodies because we now know the shape of HIV’s surface proteins, down to the atomic level. Nabel used this knowledge to identify parts that stay the same while the rest of the virus shifts and mutates. These non-mutating regions are likely to be vital areas that cannot change without causing problems. He searched patients’ blood to find antibodies that target these conserved regions, and cells that make those antibodies. In 2010, he found three: two of which could neutralise 90% of HIV viruses. Other scientists, such as Dennis Burton of the Scripps Research Institute, have made similar discoveries using similar methods.

Nabel’s vision is a cocktail of these super-antibodies that target different parts of the virus, cutting off its evolutionary escape routes. He hopes to start clinical trials of his first-generation antibodies by early 2013, and he says is close to producing a second-generation of even heavier hitters that he thinks are two to three years away from early trials.

Vaccine researchers are also working on ways of stimulating our T-cells to kill infected cells at an early stage. This was the strategy behind Merck’s failed v520 vaccine, but scientists have since found better ways of smuggling viral genes into cells, and targeting them at the tissues most likely to be infected first. Both approaches would be complementary: “I think we would need a combination of broadly neutralising antibodies and a broad and robust T-cell response,” says Koff.

Compelling need

There is no telling when, or indeed if, these strategies will yield results, but what is certain is that the need for a vaccine will not diminish. There are many ways of preventing HIV infection, including condoms, microbe-killing gels, and the use of treatments as soon as people get infected. “We’d be going in the right direction with the tools we already have,” says Fauci. “But if we added a vaccine to the toolkit, even if it wasn’t 90% effective, you could have a major additive effect. There really is a compelling need for one.”

It may seem frustrating that decades of research have yielded nothing that satisfies this compelling need. But everything in the pipeline has depended on a steadily accumulating knowledge of the virus over those years. And as much as we know about the virus, and our immune response to it, there is still a great deal to learn. Also consider this. It took 47 years to create a vaccine for polio after the microbe behind it was identified. The measles vaccine took 42 years. The hepatitis B vaccine was a positive sprint at 16 years. “Twenty-eight years isn’t an inordinate amount of time,” says Fauci.

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Early Elevated Hiv Infection Risk in Some Step Study Participants Who Received Vaccine; Risk Decreased Over Time

ScienceDaily (May 7, 2012) — A long-term follow-up analysis of participants in the Step Study, an international HIV-vaccine trial, has confirmed that certain subgroups of male study participants were at higher risk of becoming infected after receiving the experimental vaccine compared to those who received a placebo. The vaccine used in the study did not contain the HIV virus, but it did contain HIV genes which were delivered to cells using a vector that employed a type of cold virus known as adenovirus serotype 5 (Ad5).

Of the 1,836 men examined in this study, 172 became infected with HIV. Within 18 months of enrollment or one year after the last vaccination, men who had neutralizing antibodies to Ad5 or who were uncircumcised, or both, had a two- to four-fold increased risk of acquiring an HIV infection, according to findings published in the May 4 online edition issue of the Journal of Infectious Disease.

However, the study also found that the risk level waned after about 18 months to be equal to that of volunteers who received a placebo.

Why this association occurred, what the biological mechanisms were and why the risk of infection lessened with time are unknown and require more study, according to Ann Duerr, M.D., a member of the Vaccine and Infectious Disease Division of Fred Hutchinson Cancer Research Center, who led the data analysis.

"There seems to be some kind of biologic phenomena that affects infection risk," she said.

The current study indicated that self-reported risk behaviors, such as unprotected sex, did not differ significantly between the vaccine and placebo arms of the Step trial.

The research also confirmed there was no elevated risk of infection in vaccinated men who were circumcised and who were Ad 5 seronegative (men who had no neutralizing antibodies to the adenovirus vector used in the vaccine). An earlier interim analysis of the Step Study data, done after immunizations in the vaccine trial were halted in 2007, also detected this relationship between Ad5 sero-status and vaccine-associated HIV risk. Today, only men who are circumcised and Ad5 seronegative are eligible to receive experimental HIV vaccines that use the adenovirus serotype 5 as a biological delivery mechanism.

Duerr said scientists need a better understanding of what happened biologically to men who became infected, before those who are uncircumcised or seropositive for Ad 5 are enrolled in future vaccine trials in which the adenovirus serotype 5 vector is used. Ad 5 is used as a vector because it elicits a strong immune response by CD8 T cells. These cytotoxic T lymphocytes are thought to be responsible for controlling HIV infection.

In the current study, researchers analyzed data from male Step Study participants who enrolled in a trial that provided follow-up for up to four years after they enrolled in the Step study, or until Dec. 31, 2009, whichever came first.

The Step Study enrolled 3,000 male and female volunteers in North and South America, the Caribbean and Australia between 2004 and 2007. Injections in the study were halted in September 2007 after researchers detected a lack of effectiveness by the vaccine to prevent HIV acquisition or reduce HIV viral load in infected participants, and a higher-than-expected number of HIV infections in certain subgroups of vaccinees.

In addition to Hutchinson Center researchers, scientists from the San Francisco Department of Public Health, University of Washington, Emory University, Care Resource, Merck Research Laboratories and two Peruvian institutions co-authored the paper. The study was funded by Merck Research Laboratories and the National Institutes of Health.

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Senate HELP Committee to Hold Hearing on Prize Fund for HIV/AIDS Act

May 7, 2012 By Mike Palmedo

On May 15, the Senate Health, Education, Labor and Pensions Committee will hold a hearing on S. 1138, the Prize Fund for HIV/AIDS Act. The bill, introduced a year ago by Sen. Sanders, would provide direct support to innovators while allowing immediate generic competition upon approval of new treatments for HIV/AIDS.

As explained in a fact sheet from Sanders’ office: “The Prize Fund would reward useful investments in R&D for new treatment and manufacturing processes, and would lower the overall costs of treatments for HIV/AIDS by allowing introduction of generic medicines for HIV/AIDS as soon as they enter the market. The Prize would be co-funded by the federal government and private health insurance programs at 0.0002 of the GDP of the United States, equaling more than $3 billion per year at current levels. Patents would still be available for HIV/AIDS inventions, and valuable in making claims against the Prize Fund, but could not be used to block generics entering the market. Generic competition among competitive suppliers is expected to lower the cost of drugs by more than $7 billion per year for the U.S. domestic market, with the saving shared by health insurers (both public and private) and patients.”

For more see:

• Fact Sheet from Sen. Sanders’ Office
• Text of S.1138: The Prize Fund for HIV/AIDS Act
• Blog by James Love on Sanders’ introduction of this (and another) Prize fund bill

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Scarring Cells Revert To Inactive State As Liver Heals

UC San Diego School of Medicine

A photomicrograph of cirrhotic liver tissue, with extensive fibrotic scarring (stained blue).

Released:5/7/2012 3:40 PM EDT
Source:University of California, San Diego Health Sciences

Research with mice reveals possible strategy to reverse fibrosis in liver and other organs

Newswise — An international team of scientists, led by researchers at the University of California, San Diego School of Medicine, report that significant numbers of myofibroblasts – cells that produce the fibrous scarring in chronic liver injury – revert to an inactive phenotype as the liver heals. The discovery in mouse models could ultimately help lead to new human therapies for reversing fibrosis in the liver, and in other organs like the lungs and kidneys.

The work is published in the May 7, 2012 online Early Edition of the Proceedings of the National Academy of Sciences.

“The take-away message is two-fold,” said David A. Brenner, MD, vice chancellor for Health Sciences, dean of the UC San Diego School of Medicine and senior author of the paper. “First, we’ve shown that liver fibrosis is markedly reversible and we now better understand how it happens. Second, we can start looking for ways to direct active myofibroblasts to stop producing scar, and become inactive. We can focus on developing drugs that promote cell change and regression. It raises the bar for prospective treatment tremendously.”

Liver fibrosis is the 12th leading cause of death in the United States. It is the result of chronic liver injury caused by such agents as the hepatitis B and C viruses, alcoholic liver disease and non-alcoholic steatohepatitis. The condition is manifested by extensive scarring of liver tissue and the organ’s progressive inability to filter body toxins. Liver fibrosis precedes the development of liver cancer. Often, the only treatment for end-stage liver fibrosis is an organ transplant.

Fibrosis begins when infectious agents or excessive alcohol consumption trigger activation of hepatic stellate cells (HSCs), which normally act as quiescent storage units for nutrients like vitamin A in the liver. Once activated, these HSCs acquire characteristics of another cell type called myofibroblasts, which are characterized by their abundant production of extracellular matrix proteins such as collagen. These proteins accumulate as scar tissue, rendering the organ progressively dysfunctional.

However, if the source of the liver injury is successfully treated or eliminated, the liver can repair itself. In part, this is due to the activated HSCs undergoing apoptosis (programmed cell death) and being removed by other cells. But UC San Diego scientists say that, in tests using a mouse model, as many as half of all activated HSCs persist. They do not die, but rather revert to an inactive phenotype during fibrotic regression.

“After one month of regression, these cells have stopped producing collagen. They’ve upregulated some of the genes associated with quiescence and returned to their normal location in the liver,” said Tatiana Kisseleva, MD, PhD, an assistant research scientist and first author of the study.

It’s not clear why these myofibroblasts survive. Also, scientists note the reverted myofibroblasts do not completely return to their original quiescent state. “They’re still more susceptible to repetitive injury than original quiescent HSCs,” said Kisseleva, who noted future tests will investigate whether additional reversion occurs with more time.

Kisseleva suggested the findings present another avenue for treating liver fibrosis, especially in possibly reverting fibrosis and cirrhosis, which accounts for roughly 27,000 deaths in the United States annually.

Fibrosis occurs in other organs as well, such as the kidneys and lungs, with comparable deadly effect. Recent studies indicate fibrotic reversibility in these organs as well. “Our findings are applicable to other fibrosing organs,” said Kisseleva. “Instead of killing damaged cells, we might be able to de-activate them and revert them to healthy originals.”

Co-authors of the study are Min Cong, Chunyan Jiang, Keiko Iwaisako, Brian Scott and Wolfgang Dillmann, Department of Medicine, UC San Diego; YongHan Paik, Department of Medicine, UC San Diego and Department of Medicine, Sungkyunkwan University School of Medicine, Seoul, South Korea; David Scholten, Department of Medicine, UC San Diego and Department of Medicine III, University Hospital Aachen, Germany; Thomas Moore-Morris and Sylvia M. Evans, Skaggs School of Pharmacy and Pharmaceutical Science, UC San Diego; Hidekazu Tsukamoto, Keck School of Medicine, University of Southern California.

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Intensive Follow-up Reduces Mortality from Hepatocellular Cancer

By: NEIL OSTERWEIL, Family Practice News Digital Network

05/07/12

ORLANDO – Intensive follow-up of patients who have undergone surgery for hepatocellular carcinoma reduces deaths from tumor recurrence and metastases, Dr. Timothy M. Pawlik said at a symposium sponsored by the Society of Surgical Oncology.

Data from surveillance programs for hepatocellular carcinoma (HCC) and empiric data from centers treating colorectal liver metastases (CRLM) suggest that HCC tends to recur locally, and that recurrent HCC and CRLM, if caught early, can be successfully controlled with a variety of therapeutic options, said Dr. Pawlik, associate professor of surgery and oncology, and hepatobiliary surgery program director at Johns Hopkins Medical Center, Baltimore.

"I would favor high-intensity surveillance for patients with hepatocellular carcinoma. This argument is based on level 1 data showing that high-intensity primary surveillance decreases mortality for patients who have cirrhosis," he said.

Although there is a high HCC recurrence rate following surgery, most recurrences will be contained within the liver, and may be successfully treated with salvage transplantation, ablation, or intra-arterial therapy.

"But if we miss that opportunity and patients recur with advanced disease, all those options are off the table, and their prognosis is abysmal," Dr. Pawlik said.

According to National Cancer Institute data, liver cancer holds the dubious distinction of being the fastest growing cancer in terms of death rate in the United States, outpacing lung cancer in women, esophageal cancer, and thyroid cancer.

Risk factors for HCC include cirrhosis from any cause (hepatitis B and C viruses, alcoholism, nonalcoholic fatty liver disease), hepatitis B primary infection (with or without cirrhosis), and inherited metabolic diseases such as hemochromatosis, alpha-1 antitrypsin deficiency, glycogen storage disease, or tyrosinemia.

"Most patients who have HCC don’t simply have a cancer; they also have significant underlying cirrhosis, so when thinking about the approach to HCC, we have to be thinking about all of the tumor-specific factors such as tumor size, location, and number, and we also have to be thinking about all of the liver-specific factors," Dr. Pawlik said.

Surgical treatment options include resection for HCCs of all sizes; transplantation, for single lesions 5 cm or smaller, or up to three lesions of 3 cm or less or advanced cirrhosis; and ablation for small lesions or inoperable or unresectable tumors as a bridge to transplant.

In various series, overall 5-year survival following resection ranges from 42% to 62%, and following transplantation from 57% to 75%.

But as Dr. Pawlik and colleagues noted in a 2008 study, disease-free survival following resection for HCC is only half of the percentage after transplantation (40% vs. 82%, P less than .01). (J. Gastrointest. Surg. 2008;12:1699-1708).

Intrahepatic recurrence is most frequent among patients with hepatitis C infection, but also occurs with hepatitis B and C coinfection, and hepatitis B alone. A subset of patients who have undergone transplantation (about 20%) will also have recurrence, Dr. Pawlik said.

National Comprehensive Cancer Network guidelines for follow-up of patients with HCC after resection or transplantation include imaging every 3-6 months for 2 years, then every 6-12 months thereafter, and testing of alpha-fetoprotein (AFP) level, if initially elevated, on the same schedule, he noted.

For example, a trial that included 18,816 hepatitis B carriers in China randomized to either intensive surveillance with AFP level and twice-yearly ultrasound versus no screening showed that the intensive surveillance was associated with a significantly lower rate ratio for mortality compared with no screening (RR 0.63) (J. Cancer Res. Clin. Oncol. 2004;130:417-22).

Similar evidence has been found to support intensive follow-up for colorectal cancers, for which there is effective therapy for recurrent disease, Dr. Pawlik noted.

Unlike pancreatic cancer or melanoma, where recurrences tend to be distant metastases, hepatocellular carcinoma is more frequently locally recurrent. It was found that 64%-80% of patients with cirrhosis had an intrahepatic recurrence within 5 years of HCC resection.

In one study, investigators found that 60%-70% of tumors recurred within 2 years, and 30%-40% of patients with recurrences had de novo tumors (J. Hepatol. 2003;38:200-7).

"For patients who have hepatocellular carcinoma, there are two reasons to [monitor] these patients closely. One is that they may truly have recurrence, and two is that a subset of these patients will develop new de novo disease in the cirrhotic liver," Dr. Pawlik said.

Treatment options for late recurrences are very limited and not very effective, he added. Sorafenib (Nexavar) is approved for unresectable HCC, but in the phase III SHARP trial was associated with an improvement in median overall survival of only 2.8 months vs. placebo (P = .00058) (N. Engl. J. Med. 2008;359:378-90).

In contrast, early recurrences generally respond to repeat resection, salvage transplantation, radiofrequency ablation, or transarterial chemoembolization, Dr. Pawlik noted.

Dr. Pawlik said he has no relevant disclosures.

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Gilead’s Truvada Pill Is Safe for HIV Prevention, FDA Says

By Ryan Flinn and Shannon Pettypiece - May 8, 2012 10:28 AM ET

Gilead Sciences Inc. (GILD)’s pill Truvada was safe and effective when used to protect uninfected people from getting HIV, U.S. regulators said in a report indicating the main concerns are when and how it should be used.

Truvada was “well tolerated” and its ability to reduce the risk of infection was backed by two studies, the Food and Drug Administration staff said in a report today. Gilead, based in Foster City, California, is seeking to sell the drug as the first pill to keep people from becoming infected.

The FDA asked its advisers to suggest who should get Truvada; what testing would be needed for administration; and what educational material should be used for patients and doctors. The advisers will meet May 10 to discuss the drug, the subject of debates over its appropriate use and cost.

Decisions to prescribe Truvada “should carefully weigh the individual risks for acquiring HIV, their understanding of the importance of adherence to medication, and their potential for development of renal toxicity,” the FDA staff said today in a report on the agency’s website. Education and counseling will be“critically important.”

Gilead fell less than 1 percent to 9:57 a.m. New York time. The FDA isn’t required to follow what the advisory panel suggests.

AIDS Debate

Debate over the appropriate use of the drug has divided the AIDS community. Some AIDS advocacy groups say the drug will be a valuable tool for reducing new cases, particularly within stable partnerships where one person has AIDS and the other doesn’t. Others said it may lead to more infections, lower condom use and might build resistance to the medicine.

About 415,000 Americans are at high risk for contracting HIV, the Human Immunodeficiency Virus that leads to AIDS, according to the U.S. Centers for Disease Control and Prevention, based in Atlanta.

“Thirty years into the epidemic we can’t dismiss any new options,” James Loduca, a spokesman for the San Francisco AIDS Foundation, said in an interview. “This won’t end AIDS by itself, but we can’t end it without this.”

Loduca said condoms aren’t enough to stem the tide of new infections, and using Truvada as a preventative measure would help if taken correctly.

While the number of people infected with HIV rose to 34 million worldwide in 2009, the virus that leads to AIDS, once a death sentence, can be reduced to low levels in the blood with use of combination antiviral medicines such as Truvada.

Condom Use

Michael Weinstein, president of the AIDS Healthcare Foundation, said approval and prescription of Truvada as a preventative may lead to less condom use and more infections, as well as increased resistance to the drug.

“Why would you take this medication if you intended to use condoms?” he said. “You’ve got to be really paranoid about your pants falling down to wear a belt and suspenders.”

His organization sued the FDA last year after the agency rejected its Freedom of Information act request for correspondence between regulators and Gilead. Weinstein said the studies don’t prove that the pill is effective enough to warrant approval. The AIDS Healthcare Foundation has lined up speakers for the public hearing later this week to oppose its preventative use, Weinstein said.

Barry Zingman, medical director at the AIDS Center at Montefiore hospital in the Bronx, one of the largest treatment centers in New York, said he hopes the drug is approved and plans to offer it to some patients.

Pill ‘More Acceptable’

“If condoms were 100 percent effective and useful we wouldn’t have HIV at all,” Zingman said in an interview. “The reality is many people don’t like to use condoms or won’t, and taking a pill can be a lot more acceptable to them.”

He said his big concern is the drug’s more than $11,000 a year price tag.

“People are really interested in the concept, but there have been issue related to insurance coverage,” Zingman said.“Approval would make a significant advance in insurance coverage.”

Aetna Inc. spokeswoman Tammy Arnold and WellPoint Inc. spokeswoman Lori McLaughlin said their companies would consider covering the treatment as a form of prophylaxis if approved by the FDA. UnitedHealth Group Inc. declined to comment.

Medicare, the federal program for the elderly and disabled, and Medicaid, the joint state-federal plan for the poor, typically reimburse for all FDA-approved indications.

High-Risk Treatment

If approved, the drug would mostly be given to people at high risk for infection, like men who have sex with men, intravenous drug users and sex workers, said Ken Mayer, medical research director at the Fenway Institute, the largest AIDS treatment center in New England. It would typically be given for a limited period of time, he said.

“I think it would be a mistake for the FDA not to approve this indication,” Mayer said. “If we can figure out how to use this most effectively we can really put a dent in the number of new infections.”

In a study of men who have sex with men, the drug reduced the risk of infection by 42 percent, though adherence in the trail was low, the agency said. In a study of heterosexual couples where one person was infected, the risk was reduced by 75 percent.

To contact the reporters on this story: Ryan Flinn in San Francisco at rflinn@bloomberg.net; Shannon Pettypiece in New York at spettypiece@bloomberg.net

To contact the editor responsible for this story: Reg Gale at rgale5@bloomberg.net

Source

Aethlon Medical Reports Undetectable Hepatitis C Virus (HCV) in Genotype 1, Genotype 3, and Genotype 5 Patients Treated with Hemopurifier® Therapy

PRESS RELEASE

May 8, 2012, 9:30 a.m. EDT

SAN DIEGO, May 8, 2012 /PRNewswire via COMTEX/ -- Aethlon Medical, Inc. , the pioneer in developing selective therapeutic filtration devices to address infectious disease, cancer and other life-threatening conditions, reported today that the presence of Hepatitis C virus (HCV) is currently undetectable in all infected patients that have been treated with the Aethlon Hemopurifier® in combination with peginterferon+ribavirin (PR) drug therapy and monitored for at least ninety days.

In a study conducted at the Medanta Medicity Institute (Medicity), HCV-infected individuals were enrolled to receive up to three, six-hour Hemopurifier® treatments during the first three days of PR drug therapy. The Medicity is a $360 million multi-specialty medical institute established to be a premier center for medical tourism in India. The Aethlon Hemopurifier® is a first-in-class medical device that selectively targets the rapid clearance of HCV from the entire circulatory system to improve benefit, dose, duration and tolerability of drug therapies.

In the Medicity study, Aethlon reported that Hemopurifier® therapy has been well tolerated and without device-related adverse events in nine treated patients. Of these nine patients, six patients were infected with HCV genotype-1; two patients were infected with HCV genotype-3; and one patient was infected with HCV genotype-5. Of the nine reported patients, seven have been monitored for more than ninety days. All seven currently maintain undetectable viral load, including three patients who have been monitored for 48-weeks. Two patients initiated Hemopurifier® therapy on April 18th and April 30th, and therefore have not yet been monitored for extended viral load suppression.

The Immediate Impact of Hemopurifier® Therapy

In addition to demonstrating safety and early efficacy against multiple HCV genotypes, a clinical objective of the Medicity study was to evaluate whether the Hemopurifier® could accelerate HCV eradication to levels associated with treated patients who achieve the highest rate of viral cure, including individuals that previously failed or relapsed PR drug regimens. In the study, Aethlon observed that viral load depletion during the Hemopurifier® + PR drug therapy phase was greatest in hard-to-treat genotype-1 patients with high viral load. In one treated patient, baseline HCV RNA dropped from 5,800,000 IU/ml to 1,840 IU/ml when measured after the third day of Hemopurifier® + PR therapy, representing a 3.49 log or 99.96% reduction of viral load. In another patient, baseline HCV RNA dropped from 8,760,000 IU/ml to 4,665 IU/ml when measured on day-3, representing a 3.27 log or 99.96% reduction. By contrast, a moderate viral load Hemopurifier® patient with baseline HCV RNA of 1,340,000 IU/ml dropped to 54,900 IU/ml when measured on day-3, representing a 1.38 log or 95.9% reduction.

As a point of reference, the landmark IDEAL Study of 3,070 HCV genotype-1 patients documented that less than 5% of treated patients will achieve a 2-log or greater reduction of viral load when measured 7-days after the start of PR drug therapy. While the IDEAL study did not report day-3 viral load, a 2-log+ reduction at day-7 is a rare occurrence defined as an immediate virologic response (IVR). The IDEAL study confirms the viral cure or sustained virologic response rate of IVR patients to be greater than 90%. Based on Medicity treatment outcomes, Hemopurifier® therapy had a significant impact in accelerating HCV eradication in high viral load patients.

Capacity of the Hemopurifier® to Capture HCV During Treatment

As the result of discussions with reviewers at the Center for Devices and Radiological Health (the FDA branch responsible for approving medical devices in the US), Aethlon recently expanded the Medicity protocol to establish a data point that would quantify the amount of HCV captured within the Hemopurifier® during a single treatment. In one analyzed cartridge, researchers recovered and measured that approximately 300 billion (300,000,000,000) copies of HCV had been captured within the Hemopurifier® during a single six-hour treatment at the Medicity. Beyond the impact of inhibiting progeny virus replication, the viral capture data point defines the contribution Hemopurifier® therapy can provide to current and future antiviral drug treatment regimens. Aethlon considers this data point to be unprecedented as the previous ability to measure the benefit of HCV therapies has primarily been limited to measuring changes in the amount of virus that can be detected in circulation.

Next Steps

As a result of Hemopurifier® + PR therapy outcomes, Aethlon has requested permission from the Medicity internal review board (IRB) to begin offering Hemopurifier® therapy to HCV-infected individuals that reside outside of India. The Company has also requested IRB permission to expand the treatment protocol to allow for up to seven Hemopurifier® treatments to be administered during the first week of PR drug therapy. Based on previous three-treatment protocol outcomes, Aethlon anticipates an expanded Hemopurifier® dosing schedule could establish new milestones for early undetectable viral load achievement. The Company also disclosed it will resubmit an investigational device exemption (IDE) which incorporates the Medicity data as part of its effort to gain FDA approval to initiate clinical programs in the U.S.

It is estimated that approximately 4 million Americans and 170 million people worldwide are infected with HCV, which leads to chronic liver disease or cirrhosis, and is the leading cause of liver transplant in the U.S. To date, almost 100 Hemopurifier® treatments have been administered in human studies. Previously, studies of the Hemopurifier® have been conducted at the Apollo, Fortis, and Sigma New Life hospitals in India. These studies demonstrated that Hemopurifier® therapy could safely reduce viral load in both HIV and HCV-infected dialysis patients without the administration of antiviral drug therapies. The Medicity study represents the first Hemopurifier® study in non-dialysis patients. In vitro studies have further validated the ability of the Hemopurifier® to capture a broad-spectrum of viral pathogens classified as bioterror or pandemic threats.

About Aethlon Medical

The Aethlon Medical mission is to create innovative medical devices that address unmet medical needs in cancer, infectious disease, and other life-threatening conditions. Our Aethlon ADAPT(TM) System is a revenue-stage technology platform that provides the basis for a new class of therapeutics that target the selective removal of disease enabling particles from the entire circulatory system. The Aethlon ADAPT(TM) product pipeline includes the Aethlon Hemopurifier® to address infectious disease and cancer; HER2osome(TM) to target HER2+ breast cancer, and a medical device being developed under a contract with DARPA that would reduce the incidence of sepsis in combat-injured soldiers and civilians. For more information, please visit www.aethlonmedical.com .

Certain statements herein may be forward-looking and involve risks and uncertainties. Such forward-looking statements involve assumptions, known and unknown risks, uncertainties and other factors which may cause the actual results, performance or achievements of Aethlon Medical, Inc. to be materially different from any future results, performance, or achievements expressed or implied by the forward-looking statements. Such potential risks and uncertainties include, without limitation, that the FDA will not approve the initiation of the Company's clinical programs or provide market clearance of the company's products, future human studies of the Aethlon ADAPT(TM) system or the Aethlon Hemopurifier® as an adjunct therapy to improve patient responsiveness to established cancer therapies, the Company's ability to raise capital when needed, the Company's ability to complete the development of its planned products, the Company's ability to manufacture its products either internally or through outside companies and provide its services, the impact of government regulations, patent protection on the Company's proprietary technology, product liability exposure, uncertainty of market acceptance, competition, technological change, and other risk factors. In such instances, actual results could differ materially as a result of a variety of factors, including the risks associated with the effect of changing economic conditions and other risk factors detailed in the Company's Securities and Exchange Commission filings. These statements, including patient data, are based on information currently available to the Company's management and future patient results may differ from present results. The Company undertakes no obligation to publicly update or revise any forward-looking statements, whether as a result of new information, future events, or otherwise.

Contacts:

James A. JoyceChairman and CEO858.459.7800 x301jj@aethlonmedical.com 

Jim FrakesChief Financial Officer858.459.7800 x300jfrakes@aethlonmedical.com

Marc Robins877.276.2467mr@aethlonmedical.com 

SOURCE Aethlon Medical, Inc.

Source

Blood Sample Bill a Bad Idea: BC Health Officer

Emergency workers exposed to bodily fluids have better protections: Kendall.

By Andrew MacLeod, Yesterday, TheTyee.ca

Provincial Health Officer Perry Kendall has sent a letter to all British Columbia MLAs advising them against voting for a bill aimed at helping people who respond to emergencies.

The bill won't succeed at preventing any infections as it intended to, and it may well increase the risk, he said.

The Emergency Intervention Disclosure Act would allow police, firefighters and paramedics to use a court order to force someone to give a blood sample if they've been exposed to that person's bodily fluids during the course of their work.

Labour, Citizens' Services and Open Government Minister Margaret MacDiarmid, who worked as a family physician before entering politics, introduced the bill on April 30. Both government and opposition MLAs have expressed support for the bill, while noting the concerns raised by Kendall and Information and Privacy Commissioner Elizabeth Denham.

"I fully recognize that elected officials have the final authority over what they choose to enact legislatively," Kendall wrote in his May 1 letter. "But I respectfully submit that there are some substantive public health and policy issues that may not have been fully appreciated in discussions so far. I am setting out my concerns in order to ensure that your decisions may be fully informed."

No infection reduction

Kendall began by saying he has "nothing but respect" for first responders and that he recognizes the risk their work brings of exposure to blood and bodily fluids that may contain pathogens, and the anxiety those exposures can bring.

But after four pages bringing a medical perspective to the question, he concluded, "It should be apparent that the actions available under this proposed Act will in no way reduce the risk of infection or result in any fewer episodes of occupational disease transmission."

Moreover, he said, "A case could be made that passage of the Act could result in increasing such risk if an exposed First Responder relied upon knowing the infection status of the source prior to initiating post-exposure prophylaxis."

The main concerns are HIV, hepatitis B and hepatitis C, he said. "There is an alternative resolution to these concerns that obviates the need to seek a court order overruling an individual's right to refuse to submit to diagnostic testing, and alternative that has a lower likelihood of unwanted adverse consequences."

There is a vaccine for hepatitis B that all first responders should have, he said. If they are exposed, they should take immune globulin, which "virtually guarantees 100 per cent protection from recent and future exposures."

Better options for treatment

In the case of HIV, the treatment should start much quicker than the time it would take to force and get a blood test, Kendall said.

"Post-exposure prophylaxis is highly effective and with newer medications, well-tolerated, should be started within two hours, and is recommended to continue for 28 days," he said. "Waiting for test results from a source person could result in a preventable HIV infection occurring, and even a negative test result of a high risk source does not guarantee that the source is not infected due to the possibility of false negative tests."

As for hepatitis C, there is no vaccine or prophylaxis available. "Post-exposure management recommends follow up to ascertain whether infection has occurred and to institute antiviral therapy if so confirmed," Kendall wrote.

The letter notes that WorkSafeBC figures show that since 1987 there have been 47 cases the agency has followed where first responders have been exposed to blood.

"There is thus a statistically small, but very real risk, and that must be taken seriously," said Kendall. "I suggest that addressing this risk can better be done by ensuring that first responders are educated about, have access to, and utilize universal precautions, pre-exposure prophylaxis where applicable, the most up-to-date diagnostic testing technologies and evidence-based post-exposure follow up."

With the most recent testing technology, known as Polymerase Chain Reaction, an infection can be found within the first responders' own blood within two weeks, Kendall said in a May 4 interview.

Forcing a person to give a sample through a court order under the proposed law would require would likely take longer, he said. "It's hard to imagine this happening in a period of time that's less than two weeks."

Practice won't change: MacDiarmid

A new generation of testing that will give results quicker is on its way, but is not yet commonly available, said Minister MacDiarmid. "We're not there at this point."

The new law will not replace the current practice, she said. "They still take all the precautionary steps."

First responders do take precautions to prevent exposure to people's bodily fluids, but it's not always possible, she said, giving the example of a paramedic arriving at a car wreck who cuts himself badly while reaching in to help someone in the vehicle.

It's also standard to go on a prophylactic treatment right away when there's been an exposure, she said.

But first responders have said they want the peace of mind a law like the one B.C. is debating would bring, she said. "I think it's really hard to dismiss that... To say there's no benefit at all, I find that quite difficult."

In most cases people will give a sample willingly, but for those rare times when they won't first responders would like to be able to compel them, she said. In Alberta, which has a similar law, it has only been used twice, she said.

"We do recognize if someone doesn't want to reveal that information, there's a privacy element to it," she said. "It's a place where we've tried to find a balance."

The majority of the MLAs support passing the bill, she said.

Support for first responders, says NDP

Indeed, when the bill came up for second reading debate on the morning of May 3, three NDP MLAs acknowledged the concerns outlined in Kendall's letter, but said they would support the bill regardless.

They included Michelle Mungall from Nelson-Creston, Jagrup Brar from Surrey-Fleetwood and health critic Mike Farnworth.

"I think it's important that we do address some of the issues [Kendall] has raised in committee stage of the bill," said Farnworth, according to Hansard. "But I think, on balance, this is a bill that strikes just that -- the right balance between the needs of our first responders in this province and the issues around privacy. I think this bill does achieve that balance, and that's why I'm pleased to support it."

The bill sends a "strong message to first responders" in the province, he said, "that members of this House have been listening to their concerns and have put forward a piece of legislation that I think meets those needs. At the end of the day, that should be what governing is about."

Certainly the bill has the support of first responders. At least a dozen, in uniform, were in MacDiarmid's office the day she introduced the bill, and reporters received printed testimonials from 14 across the province who had been exposed to bodily fluids while on the job.

One, for example, was from Lee DePellegrin, the president of the Trail Fire Fighters, who told of a colleague who while at the station had a man spit "blood and bodily fluids" in his unprotected face. The fire fighter got treatment, but didn't have peace of mind, he said. "Although the prophylactic treatment was the responsible course of action in this case, there was and is always a doubt etched in the back of the fire fighter's mind about whether he was actually exposed to a communicable disease or not."

If the person who spat at the fire fighter had been confirmed to have an infection, "then the appropriate specific treatment for the type of exposure could have been administered, as opposed to the general prophylactic cocktail," DePellegrin said.

Had the person tested negative, "a treatment may very well have happened anyway, but the big difference is the fire fighter would have confidence that after the treatment and subsequent tests, they could live a life without doubts and fear."

Provincial Health Officer Kendall, however, pointed out that sense of reassurance may be misplaced. "It won't reduce infection," he said. "The only benefit of the knowledge would be if you could get it in time and you trusted it."

In the case of HIV, for example, knowing a person didn't have it might allow the first responder to stop taking the drug therapy sooner or to return to having sex without a condom with a regular partner. However, there's a "window period" where an infected person won't test positive, so it would not be advisable to trust that first test, he said.

The government's bill is well intentioned, he said. "For all its good intentions, it may well have negative side effects that outweigh those good intentions."

Kendall in his letter also said the bill also "carries with it the spectre of possible re-exacerbation of AIDS phobia, and the further stigmatization of certain classes of individuals."

Information and Privacy Commissioner Elizabeth Denham last week wrote to MacDiarmid saying the small benefit from the bill does not outweigh the privacy invasion of requiring a medical test, The Tyee reported. "[It] subjects individuals to a process of looking for disease that is highly privacy invasive while providing little to no demonstrable benefit to the emergency responder," she said.

Andrew MacLeod is The Tyee's Legislative Bureau Chief in Victoria. Find him on Twitter or reach him here.

Source

New Drugs Require New Terms for HCV Virologic Response

From Medscape Medical News

Daniel M. Keller, PhD

May 8, 2012 (Barcelona, Spain) — The development of drugs to treat hepatitis C virus (HCV) is progressing rapidly, but the terminology to quantify virologic response is lagging. A consortium of interested organizations is creating nomenclature for virologic responses in trials of direct-acting antiviral drugs, which are small-molecule inhibitors of viral enzymes that hold the promise of interferon-free treatment regimens.

During a poster session here at the International Liver Congress 2012, Donald Jensen, MD, professor of medicine at the University of Chicago Medical Center in Illinois, presented the rationale for and principles of the nomenclature being developed by the Hepatitis C Virus Drug Development Advisory Group (HCV DrAG).

HCV DrAG is a project of the Forum for Collaborative HIV Research, which has a subgroup devoted to HCV research with experts from the American Association for the Study of Liver Diseases, the European Association for the Study of the Liver (EASL), and the Infectious Diseases Society of America. The forum is a broad consensus panel that includes industry representatives, members of American and European drug regulatory agencies, academic investigators, and representatives of advocacy groups.

Direct-acting antiviral drugs have potent antiviral actions and appear to produce a more rapid virologic response, with or without interferon, than interferon-based regimens without the new drugs. More intuitive and flexible virologic measures are needed that can adapt to these advances in HCV treatment.

"We wanted to do this before all the new oral therapies hit the market," Dr. Jensen told Medscape Medical News.

He said current terminology can be confusing when describing virologic response to the new therapies. "We felt that there was a need to have this description of virologic responses more consistent across studies — something that could also be used in manuscripts and in clinical practice," he said. A panel of experts set out to develop a nomenclature "that was intuitive, that made sense, and that was descriptive of virologic responses during the course of therapy for hepatitis C."

Considerations for Nomenclature Development

Comparisons between drugs or regimens is difficult or impossible without a common nomenclature. The propsed nomenclature will assign a description of the time frame and the level of response to the measures, as opposed to a qualitative description such as "rapid virologic response."

The proposed terminology for key decision points in treatment trials takes into account the assay-specific lower limits of quantification of HCV RNA (as opposed to lower limits of detection), with responses defined as quantifiable or unquantifiable levels of HCV RNA.

Key components in expressing virologic response are the week of treatment, the quantifiable decline in viral load from initiation of treatment (expressed as log₁₀ decline), any lead-in treatment duration (days or weeks), and whether the target HCV RNA was detected or not. The panel explains that the lower limit of quantitation (LLOQ) of a virologic assay should be clearly specified. (One common problem in current trials is the use of different commercial assay systems.) The target may or may not be detected at levels below the LLOQ.

HCV viremia at levels less than the LLOQ in trials without a lead-in treatment period — what has been called a rapid virologic response — would now be W4U, meaning an unquantifiable HCV RNA level at week 4, whether detectable or undetectable. The old complete early virologic response will now be W12U, denoting a week 12 unquantifiable HCV RNA level.

For trials with a lead-in (LI) period at, for example, weeks 0 to 4, and unquantifiable levels at week 8 (the old rapid virologic response), the new nomenclature would specifically refer to it as LI_4w-W8U. Each term would be appended with TD or TND to denote whether target HCV RNA was detected or not detected.

One holdover from the current system is sustained virologic response (SVR).

"We decided to keep SVR...but it will be sustained virologic response with a bracket after it" to denote how long the response has been sustained, Dr. Jensen noted. "We're going to keep [it] because I think that's a concept that will be consistent with future therapies."

Having a uniform reporting system will allow the comparison of results across clinical trials. In addition, the system will be able to adapt as virologic response times become shorter. Beyond clinical trials, specific terminology will aid in the development of treatment guidelines for clinical practice.

The panel has submitted a manuscript for publication. Dr. Jensen hopes that industry will adopt the system for their clinical trials and that journals will require the system as the accepted nomenclature. The US Food and Drug Administration and the European Medicines Agency, as part of the HCV DrAG working group, have stated that they would like the nomenclature to be adopted.

Dr. Jensen predicts that in the future, if very effective drugs come along and therapy becomes standardized, many of the current or proposed measures of virologic response will go by the wayside, and patients will be treated with a fixed course of therapy with an expectation of cure, as is now common with antibiotics for many infections.

George Papatheodoridis, MD, associate professor of medicine and gastroenterology at the Medical School of Athens University, staff member at Hippokration General Hospital in Athens, Greece, and member of the EASL Governing Board Scientific Committee, told Medscape Medical News that he would like to see a consensus terminology adopted, but he does not expect that it will happen soon.

Nomenclature is not the only problem in defining a response, Dr. Papatheodoridis noted.

He referred to a presentation at the congress in which researchers found a discrepancy in the viral levels of 28% of the more than 1000 samples tested with a new polymerase chain reaction (PCR) assay and the original PCR assay. With the original assay, 75% of samples had undetectable HCV DNA; with the new assay, only about 50% did. Such a difference might be reflected in the "response-guided therapy we're using now with the telaprevir or boceprevir combination," he said.

With the drugs currently in development, the companies decide which assays to use to report their findings. "All the trials are controlled by the companies. They are not controlled by us," Dr. Papatheodoridis explained.

"Another problem, which is very relevant in clinical practice, is the timing of the HCV RNA determination," Dr. Papatheodoridis explained. We don't know if a difference of a few days is relevant. If you have some new excellent drug that achieves a 100% SVR 100%, you don't care, but these are not yet available.

Mark Thursz, MBBS, MD, professor of hepatology in the Department of Medicine at Imperial College London, United Kingdom and secretary general of EASL, agreed that measures of virologic response designed for interferon-based regimens are inadequate in an era of direct-acting antiviral drugs, "because the dynamics are much quicker now. A new set of specific targets are going to be really important when we assess how well the new drugs are working."

Dr. Jensen, Dr. Papatheodoridis, and Dr. Thursz have disclosed no relevant financial relationships.

The International Liver Congress 2012: Abstract 897. Presented April 20, 2012.

Source

Is there still a role for liver biopsy in managing hepatitis C virus infections?

Clinical Liver Disease

Volume 1, Issue 2, pages 32–35, April 2012

Review

Syed-Mohammed R. Jafri M.D.^*, Stuart C. Gordon M.D.

Article first published online: 26 APR 2012

DOI: 10.1002/cld.30

Copyright © 2012 the American Association for the Study of Liver Diseases

Abstract

Watch the interview with the authors

Watch the video presentation of this article

Answer questions and earn CME

A2M, alpha-2-macroglobulin; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BOC44, boceprevir for 44 weeks; BOC RGT, boceprevir and response-guided therapy; CDS, cirrhosis discriminant score; DAA, direct-acting antiviral; GGT, gamma-glutamyl transpeptidase; HA, hyaluronic acid; INR, international normalized ratio; ITT, intention to treat; Pbo, placebo; PIIINP, amino-terminal propeptide of type III collagen; PR48, peginterferon/ribavirin for 48 weeks; SVR, sustained virological response; T12PR, telaprevir for 12 weeks and peginterferon/ribavirin; T12/PR48, telaprevir for 12 weeks and peginterferon/ribavirin for 48 weeks; TIMP1, tissue inhibitor of metalloproteinase 1.

Current guidelines emphasize the importance of liver biopsy in the management of patients with hepatitis C because liver histology provides patients and their physicians with important prognostic information and helps to guide therapy decisions and treatment regimens.1,2 Recent improvements in antiviral therapy along with the development of alternate modes of evaluating fibrosis have led to a global reassessment of the risks and benefits and the overall wisdom of performing liver biopsy in these patients.

The presence of advanced or worsening fibrosis has traditionally served as an unequivocal indication for therapy,3 and clinicians still use the degree of fibrosis as a means for justifying therapy sooner rather than later. The availability of direct-acting antiviral (DAA) agents, which bring the promise of rapid viral negativity with therapy, intuitively appears to lessen the need for biopsy in therapeutic decision making; this is analogous to previously held perceptions about genotype 2/3 patients, who had higher sustained virological response (SVR) rates. Because of the increased efficacy of the newer regimens and even better regimens around the corner, clinicians and patients may choose to forgo biopsy with the compelling argument that the benefits of such effective therapy justify its use, even in those with minimal disease.

On the basis of the results of pivotal registration trials, the US Food and Drug Administration has suggested that therapy with DAA agents mandates an assessment of the degree of fibrosis because of the vastly different therapeutic regimens for patients with more advanced fibrosis. The recommended treatment with peginterferon/ribavirin and either telaprevir or boceprevir must be longer (48 weeks) because of the consistently lower efficacy of the therapy in patients with cirrhosis2 (Figs. 1–3). Accordingly, an assessment of the degree of fibrosis is crucial before the initiation of therapy. Treatment with interferon and ribavirin has led to higher rates of adverse events, including anemia, in the face of cirrhosis,8,9 and this information must be discussed with patients with cirrhosis before the initiation of current DAA-based therapies that include peginterferon and ribavirin.

Figure 1. SVR rates by the degree of fibrosis in the ADVANCE and ILLUMINATE studies. Abbreviations: ITT, intention to treat; PR48, peginterferon/ribavirin for 48 weeks; T12PR, telaprevir for 12 weeks and peginterferon/ribavirin. Adapted with permission from New England Journal of Medicine.4, 5

Figure 2. SVR rates for patients with bridging fibrosis or cirrhosis in the Serine Protease Inhibitor Therapy 2 trial. Abbreviations: BOC44, boceprevir for 44 weeks; BOC RGT, boceprevir and response-guided therapy; PR48, peginterferon/ribavirin for 48 weeks. Adapted with permission from Journal of Hepatology.6

Figure 3. SVR rates by the degree of fibrosis in the REALIZE trial. Abbreviations: Pbo, placebo; PR48, peginterferon/ribavirin for 48 weeks; T12/PR48, telaprevir for 12 weeks and peginterferon/ribavirin for 48 weeks. Adapted with permission from the European Association for the Study of the Liver.7

In comparison with peginterferon/ribavirin dual therapy, the telaprevir- and boceprevir-based regimens have superior efficacy,4,10-14 but the field is moving forward quite rapidly, and we are currently learning about (1) far more potent DAA agents with better pharmacokinetic profiles, (2) interferon-sparing regiments, and (3) SVR rates approaching 100%. Thus, there is the likelihood that superior regimens will become available over the next few years. As physicians and patients with hepatitis C virus ponder their options, information obtained from liver biopsy samples may greatly assist in the decision to wait yet longer for future regimens with improved efficacy, shorter durations, and lower side-effect profiles.

The establishment of the fibrosis stage remains a key parameter that guides the management of patients with chronic hepatitis C. The presence of advanced fibrosis requires future lifelong screening for the development of varices and hepatocellular carcinoma, regardless of future responses to antiviral therapy. Unfortunately, an all-too-common scenario in clinical practice is the patient with known or unknown hepatitis C who learns of his cirrhosis only after the discovery of liver cancer or a large variceal bleed. Advanced fibrosis may exist in patients with normal liver enzyme levels and synthetic parameters.15 The identification of fibrosis at biopsy can be used as a realistic justification for encouraging reduced alcohol intake and weight reduction, which are factors that would otherwise accelerate the progression to cirrhosis.16-21

For the post–liver transplant patient with chronic hepatitis C, liver biopsy information is essential not only for assessing patients for fibrosis but also for differentiating between recurrent hepatitis C–induced inflammation and acute cellular rejection. Accelerated fibrosis progression in the posttransplant patient with chronic hepatitis C leads to graft loss in up to 30% of infected patients.22-24 Preemptive antiviral therapy without the guidance of biopsy information is often precluded by cytopenias, renal insufficiency, increased side effects, and the possibility of rejection.25,26 Current guidelines suggest the initiation of therapy only after the demonstration of significant cholestasis or fibrosis on liver biopsy.1,27 Accordingly, the information gained from liver biopsy, including the demonstration of either fibrosis progression or a lack of rejection, before the institution of antiviral therapy is vital to the posttransplant care of the hepatitis C patient.

The risks of liver biopsy include severe pain, organ perforation, and bleeding.28,29 This potential for complications has generated an increasing acceptance of alternative assessments of hepatic fibrosis, especially in patients with hepatitis C (Table 1). Unfortunately, for many such panels, availability, third-party payment, or widespread clinical consensus is lacking. Fibrosis related to chronic hepatitis C progresses slowly (on average 0.15 stages per year30), and a feasible alternative to liver biopsy must be able to measure this progression over time. Evaluations using standard laboratory tests, including the aspartate aminotransferase/alanine aminotransferase ratio, the cirrhosis discriminant score, the age-platelet index, the Pohl score, the aspartate aminotransferase to platelet ratio index, and platelet counts, lack either the sensitivity or the specificity needed to be useful in clinical practice.31,34,35 In addition, these noninvasive fibrosis markers may have reduced performance in hepatitis C patients with normal alanine aminotransferase levels.36 Larger test panels, including Hepascore, Liverscore, and FibroTest, have high potential for false-positive results and are not readily available in clinical practice.32,37-39 These laboratory tests and panels have not reliably detected intermediate stages of fibrosis or the progression of fibrosis, and this is valuable information for clinical decision making.30,40 Transient elastography produces suboptimal results in obese patients and in tracking changes in fibrosis.41-43 The reproducibility of transient elastography is significantly reduced (P < 0.05) in patients with steatosis, an increased body mass index, or lower degrees of hepatic fibrosis.

Table 1. Noninvasive Markers for Liver Histological Assessments (Including Tests for Fibrosis, Necroinflammation, and Steatosis)

Test	Components	Sensitivity/Specificity for Advanced Fibrosis (%/%)
The data for this table were taken from Rockey and Bissell,30 Lackner et al.,31 Adams et al.,32 Sanai and Keeffe,33 and Sebastiani et al.36 Abbreviations: A2M, alpha-2-macroglobulin; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyl transpeptidase; HA, hyaluronic acid; INR, international normalized ratio; PIIINP, amino-terminal propeptide of type III collagen; TIMP1, tissue inhibitor of metalloproteinase 1.
FibroTest-ActiTest	Age, sex, A2M, GGT, haptoglobin, total bilirubin, apolipoprotein A1, ALT	87/59
FIBROSpect II	HA, TIMP1, A2M	83/66
European Liver Fibrosis Group algorithm	Age, PIIINP, HA, TIMP1	90/41
FibroMeter	Age, sex, A2M, HA, platelet count, AST, prothrombin	82/−
Hepascore	Age, sex, HA, A2M, GGT	67/92
AST-to-platelet ratio index	AST, platelet count	41/95
AST/ALT ratio	AST, ALT	53/100
Forns index	Age, platelet count, GGT, cholesterol	94/51
Pohl score	AST, ALT, platelets	18/98
Age-platelet index	Age, platelet count	68/55
Cirrhosis discriminant score	AST, ALT, platelet count, INR	10/100
Fibrosis prediction index	Age, AST, cholesterol, past alcohol use, insulin resistance	85/48
FibroScan	Hepatic transient elastography	64/87
FIB-4	Age, AST, ALT, platelet count	71/65

Percutaneous liver biopsy is considered the gold standard for histology assessment, yet it has a widely recognized sampling error rate as high as 20% for the detection of encircling fibrotic nodules with the evaluation of just 1/50,000 of the total organ.44 Such samples can be useful only if there are an adequate number of complete portal tracts, and with a length of 2 cm and a width of 1.4 mm, this goal is often not achieved in clinical practice. Moreover, the discordance between biopsy samples taken from right and left lobes further demonstrates the inherent limitations of this time-honored diagnostic test.44,47 Despite these challenges, a liver biopsy sample from a patient with hepatitis C in the new antiviral era remains a source of invaluable information. This information can be combined with available clinical and laboratory evidence (often surrogate markers with their own inherent limitations) to best serve the patient. A physician's or patient's reluctance to undertake the risks of biopsy should not represent a contraindication to antiviral therapy but rather should serve as the basis for a discussion of our limitations in assessing liver function and disease severity.

References

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