Research & Treatment News
February 24, 2005
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The following report seems scary at first. A significantly higher incidence of two serious types of cancer in Hepatitis C patients is certainly important. But, the normal incidence of non-hodgkin's lymphoma is just 12 cases per 100,000 worldwide in 2001. So, with double the incidence that would be just 24 cases per 100,000 Hepatitis C patients. Not exactly a widespread or common situation.
It is very important to keep reports like these in perspective.
Normal multiple myeloma incidence is approximately 6 cases per 100,000 population in the US. So, 2.5 times that, is just 15 cases per 100,000 Hepatitis C patients.
Cancer in patients with hepatitis C
24 Feb 2005
People infected with the hepatitis C virus (HCV) have a higher risk of developing non-Hodgkin's lymphoma and multiple myeloma, according to a recent study of the Swedish population. These findings are published in the March 2005 issue of Hepatology, the official journal of the American Association for the Study of Liver Diseases (AASLD). Published by John Wiley & Sons, Inc, the journal is available online via Wiley InterScience: http://www.interscience.wiley.com/journal/hepatology.
Previous studies have shown that people with HCV have a higher risk of developing cirrhosis and liver cancer, however, studies of the association between HCV and other malignancies have yielded varied and conflicting results. In Sweden, a cluster of four cases of non-Hodgkin's lymphoma in 554 HCV patients raised the question of an association between those two diseases and other related cancers in the country's population.
To evaluate this possibility, researchers, led by Ann-Sofi Duberg of Örebro University Hospital in Sweden, gathered data from the Swedish Institute for Infectious Disease Control and the Swedish Cancer Registry to examine the incidence of non-Hodgkin's lymphoma, multiple myeloma, chronic lymphatic leukemia, acute lymphatic leukemia, Hodgkin's lymphoma and thyroid cancer in the country's entire cohort of HCV patients.
For 27,150 HCV patients, the researchers modelled the date of HCV infection based on age and mode of transmission. They then collected data on the relevant cancer diagnoses among these patients for the time period from 1990 to 2000, excluding those whose HCV diagnosis was within 3 months of their cancer diagnosis. Lastly, they performed statistical analyses to compare these patients' cancer rates to those of the entire Swedish population.
They found that the risk of both non-Hodgkin's lymphoma and multiple myeloma were significantly higher compared to the general population - 1.99 and 2.54 times higher, respectively. Their risk of chronic lymphatic leukemia and thyroid cancer were not significantly higher, and the incidence of both acute lymphatic leukemia and Hodgkin's lymphoma was too low to be included.
"The majority of the non-Hodgkin's lymphoma and multiple myeloma patients were estimated to have been infected more than 15 years, which is consistent with the theory that lymphomagenesis is a slow process and non-Hodgkin's lymphoma develops after a long influence," say the authors. They suggest that the risk for HCV-related malignancy increases with time of HCV infection.
As in many countries, Sweden has had an increase in the incidence of malignant non-Hodgkin's lymphoma in recent years. As most Swedish HCV patients were born after 1950, the cancer increase might be related to long-lasting HCV infection.
In conclusion, "this is the first study of the incidence of non-Hodgkin's lymphoma, multiple myeloma, chronic lymphatic leukemia, acute lymphatic leukemia, Hodgkin's lymphoma and thyroid cancer in a nationwide cohort of HCV-infected persons," the authors report. "Although the delayed diagnosis of hepatitis C most probably has made us underestimate the risk, this study showed that the risk of B-cell non-Hodgkin's lymphoma and multiple myeloma were significantly increased."
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Article: "Non-Hodgkin's Lymphoma and Other Nonhepatic Malignancies in Swedish Patients With Hepatitis C Virus Infection," Ann-Sofi Duberg, Marie Nordström, Anna Törner, Olle Reichard, Reinhild Strauss, Ragnhild Janzon, Erik Bäck, and Karl Ekdahl, Hepatology; 41:3; March 2005 (DOI: 10.1002/hep.20608).
Posted by Ralph at 8:31 PM --- Printer-friendly version
February 23, 2005
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This marks still more progress in learning about the Hepatitis C virus. The more scientists can learn, the better the chances for finding a more effective treatment.
Public release date: 22-Feb-2005
Contact: Marcia Vital
vitalm@mail.nih.gov
301-496-3583
NIH/National Institute of Diabetes and Digestive and Kidney Diseases
Scientists replicate hepatitis C virus in laboratoryNew in vitro model system will allow study of therapeutics and virus life cycle
For the first time, scientists have replicated hepatitis C virus (HCV) in the laboratory. The ability to replicate HCV in cell culture will allow researchers to better study the life cycle and biology of this virus and to test potential antiviral compounds, which may lead to new therapies for the liver disease that results from infection with HCV.
Scientists at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), one of the National Institutes of Health (NIH), conducted the study, which appears in the Feb. 15, 2005 issue of Proceedings of the National Academy of Sciences (PNAS).
"Until recently, research on this infectious disease has suffered from the lack of a robust in vitro model system," says T. Jake Liang, M.D., Chief of the Liver Diseases Branch of the NIDDK and co-author of the study. "Our model system produced viral particles that have all the properties of the whole virus. This evidence together with an analysis of the replicated viral RNA supports a conclusion of viral replication and production."
The NIDDK group used a strain of HCV that would have applications to the greatest number of people – genotype 1, the major type of HCV of human infections worldwide and the type most resistant to current therapies. They constructed an HCV replica using a DNA copy of the original HCV single-strand RNA genome. They placed the DNA copy between two ribozymes, RNA molecules that have enzymatic function and can cleave RNA sequence at specific locations.
These two ribozymes were designed to generate the correct ends of the HCV genome and to act as start and stop buttons to gene activity. The construct was "naked," meaning that it contained only nucleic acids, the genetic material of the virus, and did not have the HCV viral envelope, a protective shell of lipids and proteins that surrounds the viral RNA in fully-formed HCV. The naked HCV construct was then placed into human liver cells in a cell culture medium.
The NIDDK scientists found evidence of HCV proteins and HCV RNA within the human liver cells in the culture. Electron microscopy showed evidence of high levels of viral particles resembling fully-formed HCV outside of the human liver cells in the culture medium. The researchers believe that the HCV construct contained within the human liver cells behaved like a true HCV infection by producing fully formed copies of the virus and releasing them from the host cell into the culture medium.
Further testing is needed before the researchers can determine if the viral particles produced in this system are in fact infectious. Also, this system only represents the tail end of the viral life cycle – viral replication, assembly and release from host cells. Another HCV model system is needed to show the beginning stages of the viral life cycle – viral entry into host cells and viral activity in the host cell before replication.
"With this cell-based system, we can screen compounds with a cell-based assay to look for inhibitors of virus replication," says Liang. "We can also apply this technique to develop model systems for other similar viruses."
HCV is a small, enveloped, single-stranded RNA virus in the family Flaviviridae. HCV is a major cause of liver disease in the United States and the world. One in a series of hepatitis viruses, HCV accounts for about 15 percent of acute hepatitis cases, 60 to 70 percent of chronic hepatitis cases, and up to 50 percent of cases of cirrhosis, end-stage liver disease, and liver cancer. Almost 4 million Americans, or 1.8 percent of the U.S. population, have antibodies to HCV indicating ongoing or previous infection with the virus. Approximately 10,000 to 12,000 deaths each year in the United States are due to HCV.
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Heller, Theo; Jonathan Auerbach; Tarice Williams; Tzivia Rachel Moreen; Allison Jazwinski; Brian Cruz; Neha Jeurkar; Ronda Sapp; Guangxiang Luo; and T. Jake Liang. "An in vitro model of hepatitis C virion production." Proceedings of the National Academy of Sciences, Vol. 102, No. 7, pp. 2579-2583.
Posted by Ralph at 6:12 PM --- Printer-friendly version
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The conclusion of this study, that HCV disguises itself to appear to be part of the patient's own immune system, is very intruiging. Not just because it helps explain why HCV becomes chronic in 85% of people who contract it, but also because many of the extrahepatic symptoms of HCV appear to be similar to certain auto immune disorders.
Autoimmune disorders are when the immune system of the body actually begins to attack the body. Is the fact that the virus disguises itself as part of the immune system partially responsible for this? It seems more research is needed. So stay tuned...
Canadian scientists may have found why hepatitis C triggers chronic infection
Helen Branswell
Canadian Press
Wednesday, February 23, 2005
TORONTO (CP) - A team of Canadian researchers believes it has unravelled the mystery of how hepatitis C evades the human immune system to cause chronic disease in about three-quarters of the people who become infected.
Their discovery provides a bright ending to the personal tragedy of the hepatitis C patient whose blood they studied, a man who became infected through a medical error in a hospital clinic.
The researchers report that the virus escapes detection because its external coat mimics immunoglobulin, one of the immune system's warriors. Further, the virus may evolve to maintain or improve its camouflage as time goes on, they suggest.
Because the immune system is set up to attack only things it considers foreign, it does not attempt to destroy the virus.
"If you want to hide in a forest, it's often good to look like a tree," explained Dr. Earl Brown, a virologist at the University of Ottawa and senior author of the paper.
The team came to its conclusions by studying blood drawn from the first infected blood donor caught by heightened screening methods put in place after Canada's tainted blood scandal. The man was so newly infected with hepatitis C that his immune system hadn't yet responded to it. As a consequence, the scientists were able to chart that response over time.
"We watched it (the virus) walk into the forest," Brown said, continuing with his metaphor.
The blood donor had become infected in an Alberta hospital in the spring of 2000 while receiving intravenous antibiotics. Now living in southeastern British Columbia, he's pleased his misfortune may help science figure out how to foil the virus.
"It was such a bizarre sequence of events that I wanted to see some good come out of it," said Randy, 47, who asked that his surname not be made public.
"This might be something that could potentially lead to a cure or a better treatment for a lot of people. And that kind of drives you along on this," said Randy, who was cleared of infection in 2003 after two courses of treatment with expensive anti-viral drugs.
However, Brown said the findings - reported in this week's issue of the journal Virology - suggest a vaccine for hepatitis C may be an elusive, even dangerous target that could backfire by prompting the immune system to attack itself.
The team, which also involves scientists from Canadian Blood Services and the Alberta provincial laboratory of public health, compared the genetic codes for the virus's envelope with those of some components of the immune system, finding areas where the virus appeared to be mimicking the body's defenders.
The findings will influence future research into not just hepatitis C but other viruses that don't provoke an extended immune response, Brown said.
"It's going to change the way (scientists) think in hepatitis C (research) for sure, and probably a bunch of other diseases. It's impossible for it not to."
Others interpreted the findings more cautiously.
"It's an intriguing hypothesis but I think at this point it's really only a hypothesis," said Dr. Jake Liang, chief of the liver diseases branch of U.S. National Institute of Diabetes and Digestive and Kidney Diseases.
Liang, an expert in viral hepatitis, said the study was well done. But he and others believe the whole notion of viral "mimicry" is overhyped.
"A lot of these hypotheses are based on very weak evidence. It does have some appeal to it. Sounds good. But very few of them have ever been proved to be causal," Liang said.
Dr. Mel Krajden of the British Columbia Centre for Disease Control said he doubted the mechanism identified is the full answer to why some hepatitis C infections become chronic.
"I'm sure it's more complex than just this," said Krajden, who heads the centre's hepatitis service.
It is estimated that about 240,000 Canadians are infected with hepatitis C, which causes inflammation of the liver that can lead to cirrhosis or liver cancer.
It spreads from person to person via contact with infected blood. Shared drug paraphernalia - needles, pipes and straws - are currently the main vehicle of transmission, though prior to changes in blood screening methods, blood transfusions were also a key source of infection. The virus can also be transmitted during sex with an infected person, although the risk is low.
In about 20 or 25 per cent of cases, people will spontaneously clear the virus. The remainder are chronically infected, though treatment with anti-viral drugs appears to cure some - though not all - cases.
Posted by Ralph at 5:52 PM --- Printer-friendly version
February 11, 2005
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The following article from HivandHepatitis.com is quite encouraging for genotype 1 patients who believe they must eradicate the virus at any cost. The article is reporting on a study report appearing in the latest issue of the medical journal, Hepatology.
Apparently, two years of high dose, severe side effect, combination therapy actually "cures" the disease in these patients. These are the best results ever reported for genotype 1.
It is especially impressive in light of the fact that the rate for current combination therapy (at lower doses) is just 40% for genotype 1.
Dr. Baker is clearly excited at the prospect of this high a postive response, but is clear in pointing out that it appears to come at a very high cost (considering the severe side effects).
Nine of 10 Chronic Hepatitis C Patients Achieve a Cure 24 Weeks Post-treatment with High Dose Ribavirin Plus Standard Dose Peginterferon Alfa-2a (Pegasys)
By Ronald Baker, PhD
Ninety percent of genotype 1 patients with a high viral load enrolled in a pilot study in Sweden achieved undetectable HCV RNA 24 weeks post-treatment with a regimen of high dose ribavirin plus standard dose peginterferon alfa-2a (Pegasys). By standard definitions, this means they were cured. Results of the small pilot study appear in the current issue of Hepatology (February 2005).
Following are selected highlights of the study and the 72-week findings:
7 men, 3 women, with mean age of 51 participated (no African Americans, no cirrhotics);
All 10 participants were genotype 1, high viral load;
Patients coinfected with HIV or other diseases were excluded;
After dose adjustments, mean daily ribavirin dose was 2,540 mg/day (1,600-4,000) at week 2 (the recommended ribavirin dose is rarely above 1,200 mg/day);
Pegasys (peginterferon alfa-2a) dosing was standard: 180 microgram weekly;
Side effects were severe, particularly anemia and hemolysis; all patients required erythropoietin, and two patients required 2 separate blood transfusions;
Treatment duration was 48 weeks;
At the 24-week post-treatment follow-up, 9 of 10 patients had undetectable HCV RNA.
Background
Ribavirin is an antiviral drug that is approved in the US and Europe for use in combination with interferon alfa for the treatment of chronic hepatitis C. The current standard of care in both the US and Europe is combination treatment with peginterferon alfa-2a (Pegasys) or 2b (Peg-Intron) plus ribavirin.
Although the mechanism of action of ribavirn with interferon is not yet completely understood, it is believed to act in synergy with interferon to contribute to significantly increasing (perhaps doubling) the sustained viral response (SVR) rate by preventing virological relapse.
While the effectiveness of antiviral therapy for chronic hepatitis C has improved, individuals with HCV genotype 1, especially those with a high viral load, still do not generally experience an SVR. The SVR rate for these individuals using the current standard of care (peginterferon alfa plus ribavirin) is about 40%.
Ribavirin Dosing
One of the most controversial issues in the management of chronic hepatitis C is the question of what is the optimal dose of ribavirin and whether higher doses of ribavirin produce more effective results than standard doses?
The current recommendation for HCV genotype 1 patients is combination treatment with once weekly peginterferon alfa plus two daily doses of ribavirin for 48 weeks. The current recommended daily dose of ribavirn depends on which brand of interferon alfa is used. In the US, in combination with Pegasys, the FDA-approved dose for ribavirin is 1,000 or 2,000 mg daily, when total body weight is less than 75 kilograms or more than 75 kilograms, respectively; when used with Peg-Intron, the FDA-approved daily dose for ribavirin is a fixed dose of 800 mg. To confuse things even further, the approved daily ribavirin dose in Europe is weight-based, with 800 mg recommended for individuals weighing less than 65 kilograms, 1000 mg for individuals weighing 65-85 kilograms, and 1200 mg for those weighing more than 85 kilograms.
The Swedish Pilot Study
In the current pilot study, the objective was to evaluate the standard dose of peginterferon alfa-2a plus a daily dose of ribavirin that was individualized and calculated from a pharmacokinetic formula based mainly on renal function. In order to reach the targeted concentration of ribavirin in the blood serum, the study participants needed a mean ribavirin dose of 2,540 mg/day (range (1,600-4,000 mg/day). This equals more than double the currently recommended daily ribavirin dose.
Inclusion/Exclusion Criteria
The inclusion criteria for the pilot study were: age >18 years, elevated alanine aminotransferase, positive anti-HCV antibody test, detectable serum HCV RNA, and a liver biopsy consistent with chronic HCV but without cirrhosis.
Patients with other forms of liver disease, active hepatitis A or hepatitis B infection, hepatocellular carcinoma, human immunodeficiency virus infection, anemia, a previous diagnosis of severe depression or other psychiatric disease, significant cardiac disease, renal disease, seizure disorders, severe retinopathy, or pregnancy were excluded from the study.
Adverse Effects
The main side effect was anemia, which was controlled with erythropoietin. Two patients required blood transfusions. However, only minor treatment interruptions occurred among the ten patients who were treated with doses of ribavirin substantially exceeding standard doses. One patient was withdrawn at week 24 because of a lack of viral response, and one patient at week 39 because of side effects, primarily interferon associated.
Conclusions
At follow-up (24 weeks post treatment), nine of ten patients had undetectable HCV RNA. The primary goal of this small pilot study was to determine feasibility and safety of the treatment, and not virological outcome. However, in this difficult-to-treat patient population with genotype 1 and a high viral load, nine of ten patients were cured by standard definitions, which seems to be a better response than that found in studies using standard ribavirin doses.
The authors conclude, “A high dose of ribavirin according to an individualized schedule is feasible but associated with more frequent and serious side effects such as anemia. The viral response merits further evaluation.”
Although the promising results of this small pilot study were striking, and seem to open up a new direction in experimentation with ribavirin dosing and its relationship to improved SVR rates, it’s hard to ignore the potentially deleterious safety issues that might be encountered by many patients using such high ribavirin doses.
As well, cost issues must be considered, not just for the peginterferon and for the high ribavirin dosing, but also for the erythropoietin and possibly blood transfusions. Still, a 90% SVR for genotype 1 patients with high viral loads! It’s a thrilling thought to contemplate!
02/11/05
Departments of Infectious Diseases, Karolinska University Hospital Huddinge, Karolinska Institute, Stockholm, Sweden; Clinical Pharmacology, Karolinska University Hospital Huddinge, Karolinska Institute, Stockholm, Sweden; Renal Medicine, Karolinska University Hospital Huddinge, Karolinska Institute, Stockholm, Sweden.
Reference
K Lindahl, L Stahle, A Bruchfeld and R Schvarcz. High-dose ribavirin in combination with standard dose peginterferon for treatment of patients with chronic hepatitis C. Hepatology 41(2): 275-279. February 2005.
Posted by Ralph at 6:29 AM --- Printer-friendly version
February 7, 2005
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The following article is from Amednews.com (American Medical News, The Newspaper For America's Physicians). This is a publication of the American Medical Association. I find it interesting to see what doctors are hearing about Hepatitis C from their own association.
Again, because genotype 1 infects approximately 70% of Americans it is important to note the success rates reported. According to this article somewhere between 30 and 40% success is being experienced with genotype 1, depending upon race (interferon combination therapy is significantly less effective for African Americans).
The article ends on an up note regarding emerging therapies---particularly protease inhibitor types (as we have previously pointed out here).
Larger gains sought in hepatitis C treatmentDespite some success, the viral disease is still the most common chronic bloodborne infection in the United States.
By Susan J. Landers, AMNews staff. Feb. 14, 2005.
Washington -- There are still gains to be made in the treatment of hepatitis C, and a recent congressional hearing on the disease as well as a National Institutes of Health workshop to discuss a vaccine to fight this liver-ravaging condition hold out hope for more progress.
"In the last 10 years, we've quadrupled the treatment response rate," said Michael Bernstein, MD, director of the Hepatitis Clinic at Coney Island Hospital in Brooklyn, N.Y.
There is now an overall success rate of about 55%, researchers say. Treatment with long-acting interferon or a combination of interferon and other antiviral drugs has made the difference.
"We are still, however, left with those unfortunate 45% who don't respond," said Adrian M. DiBisceglie, MD, chief of hepatology at Saint Louis University School of Medicine.
And that's a lot of people. Hepatitis C is the most common chronic bloodborne infection in the United States. About 4 million Americans are chronically infected, and most are not even aware of this threat to their health.
Primary care physicians have a major role to play in diagnosing the infection, so that those who can benefit from treatment will receive it in time to prevent extensive liver damage, Dr. Bernstein said. The AMA and the Centers for Disease Control and Prevention have collaborated on materials targeted to doctors and patients to help with early diagnosis.
"Hepatitis C was only identified 15 years ago, so we still have much to learn about this disease," said Rep. Tom Davis, (R, Va.), chair of the House Committee on Government Reform. Davis held a hearing on hepatitis C Dec. 14, 2004.
An NIH workshop on vaccine development was scheduled for Feb. 1 and 2.
Early warning system
Hepatitis C infection often presents no warning symptoms, and many people could have unknowingly become infected from intravenous drug use years earlier or from contaminated blood or blood products received before widespread screening for the virus began in the early 1990s.
The virus is sometimes only discovered after a patient exhibits signs of serious liver disease, such as cirrhosis or liver cancer, Davis said.
Still, the forward march of treatment has resulted in substantial gains for many of those infected. "We started out treating patients with hepatitis C in the mid-80s with interferon," Dr. DiBisceglie said. At that stage, no more than 5% to 10% of patients had a sustained virologic response, he added.
Treatment refinements made since then include the use of combination therapy with pegylated interferon and ribavirin that extends the life of interferon, thus allowing it to fight the virus longer.
Today's positive outcomes jump even higher for those infected with one of the less common viral genotypes. For those infected with genotype 2 the success rate is probably 90%, and for genotype 3, it's about 70% to 80%, Dr. Bernstein said.
However, treating genotype 1 infections, the most common of the viral types, has not met with as much success. African-Americans, for whom the cure rate is the lowest, are most frequently infected with this genotype.
But it isn't just infection with genotype 1 that is making the difference in this population, Dr. DiBisceglie said. "Even if you account for genotype, the response rate is less than in whites," he said. While about 40% of whites with the genotype respond to treatment, the level drops to 30% to 40% for African-Americans. Studies are under way to examine the possible reasons for the poorer response rate.
A lesson can be drawn from this conundrum, said Stanley M. Lemon, MD, professor of microbiology and immunology at the University of Texas Medical Branch in Galveston and director of the Hepatitis Research Center there.
That lesson is to include all populations in clinical studies, he said. "If you have selected populations that don't really need to be treated by the drug, you are going to lose valuable information."
Work also has been ongoing to develop an effective vaccine, and some candidates are currently being tested. But the complex nature of the virus presents many obstacles.
"The problem is, like the AIDS virus, the envelope proteins you would likely target mutate very quickly," Dr. Bernstein said, which makes it much more difficult to design a vaccine. In contrast, proteins in hepatitis B, for which a successful vaccine has been developed, are much less variable.
Dr. Lemon finds promise in the development of small molecule antiviral inhibitors, which have been shown to cause a sharp drop in hepatitis C viral levels in a short time. Although studies of one such drug were halted because of high toxicity, others could meet with more success. "The importance of those studies, even if that drug never makes it to market, is that small molecule therapy, antivirals like we have for HIV and herpes, are nearing reality and have incredible potential," Dr. Lemon said.
Posted by Ralph at 11:24 AM --- Printer-friendly version
February 2, 2005
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This announcement is not news to most Hepatitis C patients. We have been told about the possible long term risks associated with Hepatitis C and liver cancer has always been included among them. However, and this needs to be stated, compared to the number of patients with chronic Hepatitis C, the number of patients who develop Hepatocellular Carcinoma (liver cancer) is very small.
The huge majority of patients are not at risk. But, it doesn't hurt to behave as if we all are. That is why I always recommend choosing a lifestyle, diet, and nutritional supplementation that will protect and support your liver (along with any therapy you might choose to do---pharmaceutical or otherwise).
New entries on list of cancer-causing agentsMonday, January 31, 2005 Posted: 2:26 PM EST (1926 GMT)
WASHINGTON (AP) -- The government on Monday added 17 substances to the official list of cancer-causing agents, including the first viruses: hepatitis B and C and some human papillomaviruses that cause common sexually transmitted diseases.
Lead and lead compounds, X-rays, compounds found in grilled meats and various substances used in textile dyes, paints and inks are among the other new listings, the Department of Health and Human Services said in releasing the 11th edition of the federal Report on Carcinogens.
The additions bring to 246 the total number of substances that either are "known to be human carcinogens" or "reasonably anticipated to be human carcinogens." The report now lists 58 "known" -- including the viruses -- and 188 "reasonably anticipated" substances.
Hepatitis B and C, which cause liver disease, were added because studies in humans show that chronic infections cause liver cancer. Some of the human papillomaviruses, which are sexually transmitted, were included because studies show they cause cervical cancer in women, the department said.
Federal law requires the HHS secretary to publish the report every two years.
Posted by Ralph at 7:25 AM --- Printer-friendly version
