Marcos Rojkinda, George Philipsb, Anna Mae Diehlb
Received 27 August 2010; accepted 1 September 2010. published online 04 October 2010.
Uncorrected Proof
COMMENTARY ON:
Prediction and validation of cell alignment along microvessels as order principle to restore tissue architecture in liver regeneration. Hoehme S, Brulport M, Bauer A, Bedawy E, Schormann W, Hermes M, Puppe V, Gebhardt R, Zellmer S, Schwarz M, Bockamp E, Timmel T, Hengstler JG, Drasdo D. Proc Natl Acad Sci USA 2010 Jun 8;107(23):10371–10376. Copyright (2010) by the National Academy of Sciences; USA. Abstract reprinted with permission from the National Academy of Sciences.
Only little is known about how cells coordinately behave to establish functional tissue structure and restore microarchitecture during regeneration. Research in this field is hampered by a lack of techniques that allow quantification of tissue architecture and its development. To bridge this gap, we have established a procedure based on confocal laser scans, image processing, and three-dimensional tissue reconstruction, as well as quantitative mathematical modeling. As a proof of principle, we reconstructed and modeled liver regeneration in mice after damage by CCl(4), a prototypical inducer of pericentral liver damage. We have chosen the regenerating liver as an example because of the tight link between liver architecture and function: the complex microarchitecture formed by hepatocytes and microvessels, i.e. sinusoids, ensures optimal exchange of metabolites between blood and hepatocytes. Our model captures all hepatocytes and sinusoids of a liver lobule during a 16day regeneration process. The model unambiguously predicted a so-far unrecognized mechanism as essential for liver regeneration, whereby daughter hepatocytes align along the orientation of the closest sinusoid, a process which we named “hepatocyte-sinusoid alignment” (HSA). The simulated tissue architecture was only in agreement with the experimentally obtained data when HSA was included into the model and, moreover, no other likely mechanism could replace it. In order to experimentally validate the model of prediction of HSA, we analyzed the three-dimensional orientation of daughter hepatocytes in relation to the sinusoids. The results of this analysis clearly confirmed the model prediction. We believe our procedure is widely applicable in the systems biology of tissues.
a Department of Biochemistry and Molecular Biology, George Washington University Medical Center, Washington, DC, United States
b Division of Gatroenterology, Duke University Medical Center, Durham, NC, United States
Corresponding author.
PII: S0168-8278(10)00846-9
doi:10.1016/j.jhep.2010.09.004
© 2010 Published by Elsevier Inc.
Source
October 5, 2010
Clinical trial: oral zinc in hepatic encephalopathy
Aliment Pharmacol Ther. 2010 Sep 3. doi: 10.1111/j.1365-2036.2010.04448.x. [Epub ahead of print]
Takuma Y, Nouso K, Makino Y, Hayashi M, Takahashi H.
Department of Gastroenterology, Kurashiki Central Hospital, Okayama, Japan. Department of Internal Medicine, National Hospital Organization Iwakuni Center, Yamaguchi, Japan. Department of Molecular Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan. Department of Clinical Research, National Hospital Organization Iwakuni Clinical Center, Yamaguchi, Japan.
Abstract
Background Hepatic encephalopathy has a negative effect on patient health-related quality of life (HRQOL). Zinc supplementation has been effective with regard to altered nitrogen metabolism. Aim To investigate the effectiveness of oral zinc supplementation on hepatic encephalopathy and HRQOL. Methods Seventy-nine cirrhotic patients with hepatic encephalopathy were randomized to receive 225 mg of polaprezinc in addition to standard therapies of a protein-restricted diet including branched-chain amino acid and lactulose, or to continue only standard therapies for 6 months. The change of HRQOL by Short Form-36, hepatic encephalopathy grade, laboratory parameters, and neuropsychological (NP) tests were compared at baseline and at 6 months. We also evaluated via multivariate analysis whether zinc supplementation and clinical variables correlated with the changes in physical component scale (PCS) and mental component scale (MCS) between the two visits. Results Zinc supplementation significantly improved the PCS (P = 0.04), but not the MCS (P = 0.95). Zinc supplementation significantly decreased hepatic encephalopathy grade and blood ammonia levels (P = 0.03 and P = 0.01), and improved Child-Pugh score and NP tests compared with standard therapy (P = 0.04 and P = 0.02). In multivariate analysis, zinc supplementation was significantly associated with improvement in PCS (P = 0.03), whereas it was not significantly associated with change in MCS (P = 0.98). Conclusion Zinc supplementation is effective in hepatic encephalopathy and consequently improves patients HRQOL.
PMID: 20822500 [PubMed - as supplied by publisher]
Source
Takuma Y, Nouso K, Makino Y, Hayashi M, Takahashi H.
Department of Gastroenterology, Kurashiki Central Hospital, Okayama, Japan. Department of Internal Medicine, National Hospital Organization Iwakuni Center, Yamaguchi, Japan. Department of Molecular Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan. Department of Clinical Research, National Hospital Organization Iwakuni Clinical Center, Yamaguchi, Japan.
Abstract
Background Hepatic encephalopathy has a negative effect on patient health-related quality of life (HRQOL). Zinc supplementation has been effective with regard to altered nitrogen metabolism. Aim To investigate the effectiveness of oral zinc supplementation on hepatic encephalopathy and HRQOL. Methods Seventy-nine cirrhotic patients with hepatic encephalopathy were randomized to receive 225 mg of polaprezinc in addition to standard therapies of a protein-restricted diet including branched-chain amino acid and lactulose, or to continue only standard therapies for 6 months. The change of HRQOL by Short Form-36, hepatic encephalopathy grade, laboratory parameters, and neuropsychological (NP) tests were compared at baseline and at 6 months. We also evaluated via multivariate analysis whether zinc supplementation and clinical variables correlated with the changes in physical component scale (PCS) and mental component scale (MCS) between the two visits. Results Zinc supplementation significantly improved the PCS (P = 0.04), but not the MCS (P = 0.95). Zinc supplementation significantly decreased hepatic encephalopathy grade and blood ammonia levels (P = 0.03 and P = 0.01), and improved Child-Pugh score and NP tests compared with standard therapy (P = 0.04 and P = 0.02). In multivariate analysis, zinc supplementation was significantly associated with improvement in PCS (P = 0.03), whereas it was not significantly associated with change in MCS (P = 0.98). Conclusion Zinc supplementation is effective in hepatic encephalopathy and consequently improves patients HRQOL.
PMID: 20822500 [PubMed - as supplied by publisher]
Source
Cal State Long Beach gets grant to study faster HIV, syphilis, hepatitis C tests
By Kelly Puente, Staff Writer
Posted: 10/04/2010 04:12:08 PM PDT
Updated: 10/04/2010 04:59:32 PM PDT
LONG BEACH - Cal State Long Beach has been awarded a $1.7 million research grant to study the accuracy and acceptability of rapid tests for HIV, hepatitis C and syphilis, officials said.
Through rapid testing a patient is able to receive results on the same day they are tested.
Currently, there are no rapid tests available in the United States for syphilis or combined tests for HIV and hepatitis C. While the there are rapid tests available for HIV, newer, more accurate tests have been developed and are awaiting approval from the Federal Drug Administration.
Officials say rapid testing could increase the number of those receiving test results and could in turn help prevent the spread of infectious diseases.
"Traditional testing for infectious diseases requires clients to return for their test results one or two weeks after providing a sample. But, there are many people who don't return to get their results," said Dennis Fisher, director of behavioral research at Cal State Long Beach. "We believe this project can have a significant impact on the future of screening for infectious diseases in the U.S."
The project, which started on Thursday, will help the FDA gain a better understanding of who selects rapid tests and why. It could lead to the FDA's approval of the experimental tests, officials said.
The project will examine the accuracy and acceptability of six rapid tests for HIV, syphilis, and/or hepatitis C among high-risk groups including gay men, bisexual men and injection drug users.
Fisher believes the combined test for HIV and hepatitis C could be especially helpful in preventing the spread of disease among injected-drug users because it encourages HIV testing in the population.
The four-year grant for the school's Center for Behavioral Research and Services was funded by the National Institute on Drug Abuse.
kelly.puente@presstelegram.com, (562) 499-1305
Source
Posted: 10/04/2010 04:12:08 PM PDT
Updated: 10/04/2010 04:59:32 PM PDT
LONG BEACH - Cal State Long Beach has been awarded a $1.7 million research grant to study the accuracy and acceptability of rapid tests for HIV, hepatitis C and syphilis, officials said.
Through rapid testing a patient is able to receive results on the same day they are tested.
Currently, there are no rapid tests available in the United States for syphilis or combined tests for HIV and hepatitis C. While the there are rapid tests available for HIV, newer, more accurate tests have been developed and are awaiting approval from the Federal Drug Administration.
Officials say rapid testing could increase the number of those receiving test results and could in turn help prevent the spread of infectious diseases.
"Traditional testing for infectious diseases requires clients to return for their test results one or two weeks after providing a sample. But, there are many people who don't return to get their results," said Dennis Fisher, director of behavioral research at Cal State Long Beach. "We believe this project can have a significant impact on the future of screening for infectious diseases in the U.S."
The project, which started on Thursday, will help the FDA gain a better understanding of who selects rapid tests and why. It could lead to the FDA's approval of the experimental tests, officials said.
The project will examine the accuracy and acceptability of six rapid tests for HIV, syphilis, and/or hepatitis C among high-risk groups including gay men, bisexual men and injection drug users.
Fisher believes the combined test for HIV and hepatitis C could be especially helpful in preventing the spread of disease among injected-drug users because it encourages HIV testing in the population.
The four-year grant for the school's Center for Behavioral Research and Services was funded by the National Institute on Drug Abuse.
kelly.puente@presstelegram.com, (562) 499-1305
Source
A conversation with Dr. Grace McComsey, Rainbow Babies pediatric HIV/AIDS researcher
Published: Tuesday, October 05, 2010, 4:00 AM Updated: Tuesday, October 05, 2010, 6:32 AM
Angela Townsend, The Plain Dealer
A Q&A with Dr. Grace McComsey, chief Pediatric Infectious Diseases, Rheumatology, and Global Health at University Hospitals Rainbow Babies & Children's Hospital.
What is the life expectancy of a child born with HIV/AIDS?
The answer is not known. It's still short of the normal population because of co-morbidities like heart disease, liver disease, kidney disease. Any patient who is compliant with treatments is expected to live [a relatively normal life expectancy.] But the two big co-morbidities are heart disease and cancers.
Is HIV preventable in unborn babies?
Yes. Pediatric HIV is 100 percent preventable. That's why screening is so important. If a mother takes her medications and complies with treatment, yes.
What is the status of HIV studies involving children?
Any research of kids and HIV always lags behind adults.
For cardiovascular disease, my group tried to get ahead of the curve. Initially, we had a hard time getting funding [because of] all of this skepticism of the cardiovascular disease risk in kids. But we've already generated several papers and we've really changed the mentality of doctors treating patients.
Is there really a cardiovascular risk in children?
The youngest person [at Rainbow] who had a heart attack was a 24-year-old with HIV. It's true that a 10- or 15-year-old is not having a heart attack, but a 24-year-old with no risk factor had a huge heart attack. This was 4-5 years ago. At that time, we were not as aware as we are now.
Who are the pediatric HIV patients in your study? [Note: McComsey is leading a four-year study that is trying to determine the causes of heart problems in HIV-positive children].
All but one was born with HIV. They all started medication early on. They average [nine years of taking medication] by the time the study started.
Their viral loads are very low. They are doing well from an HIV point of view.
Their CD4 count (the number of CD4 cells a blood sample; the higher the number, the better one's immune system is able to fight off the disease) is very good. This is a good population, a compliant population. No opportunistic infections.
A lot of (the patients) were obese. People have worried so much about wasting that now they don't watch what they eat. They're at the other extreme now.
[Note: Wasting is a condition marked in AIDS patients by the loss of at least 10 percent of one's body weight, and/or severe diarrhea, weakness and fever.]
What have been some of the medical gains in diagnosing and treating newborns and babies?
The diagnosis used to be that you can't really rule out HIV until the child is 18 months of age. You could carry the antibody and [not have it show up] until 18 months. Now we can diagnose by 3 months. I can tell 100 percent if they have it or not when they are born with a blood test when they're born, another blood test at 1 month and a third test at 3 months.
[Note: HIV testing at birth is not done automatically. Parental consent must be provided before the test can be administered.]
Is there a typical regimen of drugs for kids?
There are three different medications, sometimes four, to start. They have to take them twice a day, in contrast with adults who could take one pill, once a day.
At Rainbow, the youngest kid in the study was treated at 9 days old, as soon as he was diagnosed with HIV. You don't want the immune system to take a hit. We can give them oral medications through a tube.
How does treating children differ from treating adults?
Taking care of HIV-infected kids is harder. There are very few drugs in suspension (liquid) form. Domestically, they're not available. All of the money for pediatric HIV [care] is going overseas. We still have a domestic issue.
How do the drugs and the HIV itself impact other areas of health in children?
The long term complications of HIV treatment in kids and adults include lipodystrophy (an abnormal change in body composition with either fat loss or fat build up) due to old medications such as AZT. It also causes mitochondrial toxicity (damage that decreases the number of mitochondria, which provide the body's cells with energy) which is shown to increase depression and decrease quality of life.
Kids stop taking their meds because of lipodystrophy. These meds are keeping them alive but there are complications. In adults we're using newer drugs but in kids we are obligated to use the older drugs.
Tenofovir has really replaced AZT but it does not come in suspension form for kids.
How did you get into this field?
I trained at Case in infectious diseases at a time when we had a lot of sick HIV patients. During my training we lost five HIV kids. Sometimes some cases really hit you. One was a 10-year-old, so cute! I just saw him wasting and wasting, and then dying. He was a hemophiliac and got it through a blood transfusion. It just broke my heart.
HIV is really my passion. I wanted to make a difference. That's why I got into that field.
-- Angela Townsend
Source
Angela Townsend, The Plain Dealer
A Q&A with Dr. Grace McComsey, chief Pediatric Infectious Diseases, Rheumatology, and Global Health at University Hospitals Rainbow Babies & Children's Hospital.
What is the life expectancy of a child born with HIV/AIDS?
The answer is not known. It's still short of the normal population because of co-morbidities like heart disease, liver disease, kidney disease. Any patient who is compliant with treatments is expected to live [a relatively normal life expectancy.] But the two big co-morbidities are heart disease and cancers.
Is HIV preventable in unborn babies?
Yes. Pediatric HIV is 100 percent preventable. That's why screening is so important. If a mother takes her medications and complies with treatment, yes.
What is the status of HIV studies involving children?
Any research of kids and HIV always lags behind adults.
For cardiovascular disease, my group tried to get ahead of the curve. Initially, we had a hard time getting funding [because of] all of this skepticism of the cardiovascular disease risk in kids. But we've already generated several papers and we've really changed the mentality of doctors treating patients.
Is there really a cardiovascular risk in children?
The youngest person [at Rainbow] who had a heart attack was a 24-year-old with HIV. It's true that a 10- or 15-year-old is not having a heart attack, but a 24-year-old with no risk factor had a huge heart attack. This was 4-5 years ago. At that time, we were not as aware as we are now.
Who are the pediatric HIV patients in your study? [Note: McComsey is leading a four-year study that is trying to determine the causes of heart problems in HIV-positive children].
All but one was born with HIV. They all started medication early on. They average [nine years of taking medication] by the time the study started.
Their viral loads are very low. They are doing well from an HIV point of view.
Their CD4 count (the number of CD4 cells a blood sample; the higher the number, the better one's immune system is able to fight off the disease) is very good. This is a good population, a compliant population. No opportunistic infections.
A lot of (the patients) were obese. People have worried so much about wasting that now they don't watch what they eat. They're at the other extreme now.
[Note: Wasting is a condition marked in AIDS patients by the loss of at least 10 percent of one's body weight, and/or severe diarrhea, weakness and fever.]
What have been some of the medical gains in diagnosing and treating newborns and babies?
The diagnosis used to be that you can't really rule out HIV until the child is 18 months of age. You could carry the antibody and [not have it show up] until 18 months. Now we can diagnose by 3 months. I can tell 100 percent if they have it or not when they are born with a blood test when they're born, another blood test at 1 month and a third test at 3 months.
[Note: HIV testing at birth is not done automatically. Parental consent must be provided before the test can be administered.]
Is there a typical regimen of drugs for kids?
There are three different medications, sometimes four, to start. They have to take them twice a day, in contrast with adults who could take one pill, once a day.
At Rainbow, the youngest kid in the study was treated at 9 days old, as soon as he was diagnosed with HIV. You don't want the immune system to take a hit. We can give them oral medications through a tube.
How does treating children differ from treating adults?
Taking care of HIV-infected kids is harder. There are very few drugs in suspension (liquid) form. Domestically, they're not available. All of the money for pediatric HIV [care] is going overseas. We still have a domestic issue.
How do the drugs and the HIV itself impact other areas of health in children?
The long term complications of HIV treatment in kids and adults include lipodystrophy (an abnormal change in body composition with either fat loss or fat build up) due to old medications such as AZT. It also causes mitochondrial toxicity (damage that decreases the number of mitochondria, which provide the body's cells with energy) which is shown to increase depression and decrease quality of life.
Kids stop taking their meds because of lipodystrophy. These meds are keeping them alive but there are complications. In adults we're using newer drugs but in kids we are obligated to use the older drugs.
Tenofovir has really replaced AZT but it does not come in suspension form for kids.
How did you get into this field?
I trained at Case in infectious diseases at a time when we had a lot of sick HIV patients. During my training we lost five HIV kids. Sometimes some cases really hit you. One was a 10-year-old, so cute! I just saw him wasting and wasting, and then dying. He was a hemophiliac and got it through a blood transfusion. It just broke my heart.
HIV is really my passion. I wanted to make a difference. That's why I got into that field.
-- Angela Townsend
Source
Hepatitis C Drugs Rated By Consumer Reports
10/4/2010 11:44 AM ET
(RTTNews) - Consumer Reports has published recommendations regarding two drugs used in the treatment of Hepatitis C.
Consumer Reports analyzed the evidence for PegIntron and Pegasys, and found that neither has been shown to be more effective than the other. The magazine said that the two drugs do vary considerably, however, when it comes to price.
PegIntron could save consumers hundreds to thousands of dollars over Pegasys, depending on the dose and length of treatment.
The pegylated interferons can help eliminate the virus from the body, but they are very expensive, costing between $15,000 and $30,000 for a course of treatment.
These drugs can also cause a wide range of side effects, Consumer Reports points out, including flu-like symptoms such as muscle aches, fever, fatigue, depression, diarrhea, nausea, and rashes or other skin-related problems. Life-threatening or fatal problems are rare but include suicide, relapse of drug abuse or overdose and liver failure.
Hepatitis C, which afflicts an estimated four million people in the U.S., can lead to liver damage and death. It is contracted by exposure to contaminated blood and other bodily fluids.
by RTT Staff Writer
For comments and feedback: contact editorial@rttnews.com
Source
(RTTNews) - Consumer Reports has published recommendations regarding two drugs used in the treatment of Hepatitis C.
Consumer Reports analyzed the evidence for PegIntron and Pegasys, and found that neither has been shown to be more effective than the other. The magazine said that the two drugs do vary considerably, however, when it comes to price.
PegIntron could save consumers hundreds to thousands of dollars over Pegasys, depending on the dose and length of treatment.
The pegylated interferons can help eliminate the virus from the body, but they are very expensive, costing between $15,000 and $30,000 for a course of treatment.
These drugs can also cause a wide range of side effects, Consumer Reports points out, including flu-like symptoms such as muscle aches, fever, fatigue, depression, diarrhea, nausea, and rashes or other skin-related problems. Life-threatening or fatal problems are rare but include suicide, relapse of drug abuse or overdose and liver failure.
Hepatitis C, which afflicts an estimated four million people in the U.S., can lead to liver damage and death. It is contracted by exposure to contaminated blood and other bodily fluids.
by RTT Staff Writer
For comments and feedback: contact editorial@rttnews.com
Source
October 4, 2010
NVHR Blasts Arizona Medicaid's 'Inhumane' Policy Depriving Hepatitis C Patients Liver Transplant Coverage
Patient Advocates, Noted Liver Physician Criticize Arizona Policy as Lacking Scientific Basis
WASHINGTON, Oct. 4 /PRNewswire-USNewswire/ -- A controversial new policy by the Arizona Health Care Cost Containment System depriving hepatitis C patients coverage for liver transplants is effectively a death sentence that, left unchecked, could have far-reaching consequences for millions of Americans afflicted with chronic viral hepatitis, the National Viral Hepatitis Roundtable (NVHR) said today. The new coverage exclusion governing liver transplants took effect Friday as part of broader Medicaid coverage changes made by the state of Arizona in response to budgetary pressures.
"The Arizona Medicaid program's decision to deprive hepatitis C patients coverage for liver transplants is inhumane and will have devastating consequences for Arizona's Medicaid beneficiaries," said Ms. Lorren Sandt, NVHR Chair and Executive Director of Caring Ambassadors Program, based in Portland, Oregon. "NVHR recognizes that both public and private health care programs are struggling with the burden of rising costs and a challenging economic environment. However, the cruel costs associated with Arizona's Medicaid coverage changes do not appear to be based on sound science and far exceed any supposed benefit."
"The standard of care for centers and practitioners is to offer liver transplants to patients with hepatitis C. All insurance providers – including state Medicaid programs – need to provide coverage for what is the standard of care. With new curative therapies on the horizon, it is imperative not to discriminate against patients with hepatitis C when selecting patients for a liver transplant," said Robert G. Gish, M.D., Co-Director Center for Hepatobiliary Disease and Abdominal Transplantation (CHAT), University of California, San Diego School of Medicine.
Arizona Medicaid's transplant coverage exclusion is the first of its kind in the nation for hepatitis C patients. NVHR is deeply troubled that the new Medicaid coverage exclusion inflicts catastrophic consequences that go far beyond any supposed savings. According to news reports, Arizona faces a budgetary shortfall this year of as much as $825 million. The entire package of Medicaid benefit changes, including the hepatitis C liver transplant exclusion, is expected to yield about $5 million in savings – or about 1/2 of one percent of the projected budgetary shortfall.
An estimated 5.3 million Americans have been infected with chronic viral hepatitis B or C – and with most unaware of their infection, millions are at risk of developing life-threatening complications, especially African Americans and Asian Americans. Without detection and prompt treatment, chronic viral hepatitis leads to liver cancer, cirrhosis, or liver failure.
NVHR is a coalition of more than 170 public, private, and voluntary organizations dedicated to reducing the incidence of infection, morbidity, and mortality from chronic viral hepatitis that afflicts more than 5 million Americans. http://www.nvhr.org/
SOURCE National Viral Hepatitis Roundtable
RELATED LINKS
http://www.nvhr.org/
Source
WASHINGTON, Oct. 4 /PRNewswire-USNewswire/ -- A controversial new policy by the Arizona Health Care Cost Containment System depriving hepatitis C patients coverage for liver transplants is effectively a death sentence that, left unchecked, could have far-reaching consequences for millions of Americans afflicted with chronic viral hepatitis, the National Viral Hepatitis Roundtable (NVHR) said today. The new coverage exclusion governing liver transplants took effect Friday as part of broader Medicaid coverage changes made by the state of Arizona in response to budgetary pressures.
"The Arizona Medicaid program's decision to deprive hepatitis C patients coverage for liver transplants is inhumane and will have devastating consequences for Arizona's Medicaid beneficiaries," said Ms. Lorren Sandt, NVHR Chair and Executive Director of Caring Ambassadors Program, based in Portland, Oregon. "NVHR recognizes that both public and private health care programs are struggling with the burden of rising costs and a challenging economic environment. However, the cruel costs associated with Arizona's Medicaid coverage changes do not appear to be based on sound science and far exceed any supposed benefit."
"The standard of care for centers and practitioners is to offer liver transplants to patients with hepatitis C. All insurance providers – including state Medicaid programs – need to provide coverage for what is the standard of care. With new curative therapies on the horizon, it is imperative not to discriminate against patients with hepatitis C when selecting patients for a liver transplant," said Robert G. Gish, M.D., Co-Director Center for Hepatobiliary Disease and Abdominal Transplantation (CHAT), University of California, San Diego School of Medicine.
Arizona Medicaid's transplant coverage exclusion is the first of its kind in the nation for hepatitis C patients. NVHR is deeply troubled that the new Medicaid coverage exclusion inflicts catastrophic consequences that go far beyond any supposed savings. According to news reports, Arizona faces a budgetary shortfall this year of as much as $825 million. The entire package of Medicaid benefit changes, including the hepatitis C liver transplant exclusion, is expected to yield about $5 million in savings – or about 1/2 of one percent of the projected budgetary shortfall.
An estimated 5.3 million Americans have been infected with chronic viral hepatitis B or C – and with most unaware of their infection, millions are at risk of developing life-threatening complications, especially African Americans and Asian Americans. Without detection and prompt treatment, chronic viral hepatitis leads to liver cancer, cirrhosis, or liver failure.
NVHR is a coalition of more than 170 public, private, and voluntary organizations dedicated to reducing the incidence of infection, morbidity, and mortality from chronic viral hepatitis that afflicts more than 5 million Americans. http://www.nvhr.org/
SOURCE National Viral Hepatitis Roundtable
RELATED LINKS
http://www.nvhr.org/
Source
Dynavax's HEPLISAV Demonstrates Superior Seroprotection in Diabetics Compared to Engerix-B
Late-Breaker AASLD Abstract and New Diabetic Data Published Online
BERKELEY, CA, Oct 04, 2010 (MARKETWIRE via COMTEX) -- In an abstract published today on the website of the 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD), Dynavax Technologies Corporation /quotes/comstock/15*!dvax/quotes/nls/dvax (DVAX 1.89, +0.03, +1.61%) reported that its novel hepatitis B vaccine candidate, HEPLISAV(TM), given as two doses over four weeks demonstrated superior seroprotection in persons with diabetes mellitus compared to Engerix-B given as three doses over 24 weeks. The subset analysis of 62 adults with diabetes in Dynavax's previously reported Phase 3 multicenter study (PHAST or Phase 3 HEPLISAV Short-regimen Trial), showed that at 12 weeks, 84 percent of adult diabetics treated with HEPLISAV achieved seroprotection as compared to 0 percent of adult diabetics treated with Engerix-B. At week 28, 93 percent of the HEPLISAV-treated group versus 35 percent in the Engerix-B group achieved seroprotection. HEPLISAV's significantly higher rate of seroprotection was achieved without further immunization past four weeks while the Engerix-B group received a third immunization at 24 weeks. A poster presentation (LB-17) entitled, "Immunogenicity of Two Doses of Investigational HEPLISAV(TM) Compared to Three Doses of Licensed Hepatitis B Vaccine (ENGERIX-B(R)) in Diabetics", will be made in a late-breaker session on November 1, 2010 at the AASLD in Boston, Massachusetts.
According to Dr. Tyler Martin, President and Chief Medical Officer of Dynavax, "Diabetics are at risk for hepatitis B infection, and once infected, their disease frequently results in more severe chronic illness. The situation is complicated by the fact that patients with diabetes commonly do not respond well to currently licensed hepatitis B vaccines. The data we will report at the AASLD meeting is particularly exciting as our technology clearly represents a potential breakthrough in immunization regimens as well as a means of significantly expanding the number of individuals for whom protection against hepatitis B will be possible.
"It is well known that epidemic outbreaks of hepatitis B have occurred over the last several years in long-term care facilities. However, vaccination against the disease has been limited because patients in this setting simply do not respond to vaccination as well as healthy, younger adults in the general population. The Center for Disease Control and Prevention's Advisory Committee on Immunization Practices (ACIP) has been studying the issue for quite some time, and later this month will consider a new recommendation for hepatitis B vaccination of adults with diabetes," Dr. Martin continued.
Dynavax first reported the results of its PHAST multi-center, observer-blinded Phase 3 study in August 2008. Of the 2101 subjects in the overall per protocol study population, the seroprotection rate of the HEPLISAV-treated group was 95 percent at week 12 and 81 percent at week 28 in the Engerix-B group, indicating non-inferiority/superiority of HEPLISAV over Engerix-B. HEPLISAV is Dynavax's novel hepatitis B vaccine candidate, a TLR9 agonist; Engerix-B is a commercially available hepatitis B vaccine.
Engerix-B(R) is a registered trademark of GlaxoSmithKline
About HEPLISAV
HEPLISAV is an investigational adult hepatitis B vaccine. The vaccine candidate is being evaluated in two Phase 3 studies that are directed toward fulfilling licensure requirements in U.S., Canada and Europe. In a completed pivotal Phase 3 trial, HEPLISAV demonstrated increased, rapid protection with fewer doses than current licensed vaccines. Dynavax has worldwide commercial rights to HEPLISAV and is developing the vaccine for large, high-value populations that are less responsive to current licensed vaccines, including individuals with chronic kidney disease. HEPLISAV combines hepatitis B surface antigen with a proprietary Toll-like Receptor 9 agonist known as ISS to enhance the immune response.
About Dynavax
Dynavax Technologies Corporation, a clinical-stage biopharmaceutical company, discovers and develops novel products to prevent and treat infectious diseases. The Company's lead product candidate is HEPLISAV, an investigational adult hepatitis B vaccine designed to enhance protection more rapidly and with fewer doses than current licensed vaccines. For more information visit http://www.dynavax.com/.
Forward Looking Statements
This press release contains "forward-looking statements," including the potential for use of HEPLISAV that are subject to a number of risks and uncertainties. Actual results may differ materially from those set forth in this press release due to the risks and uncertainties inherent in our business, including whether the reported results can be replicated in prospective studies, whether successful clinical and regulatory development and approval of HEPLISAV can occur in a timely manner or without significant additional studies or difficulties or delays in development or clinical trial enrollment, whether the studies can support registration for commercialization of HEPLISAV; the results of clinical trials and the impact of those results on the initiation and completion of subsequent trials and issues arising in the regulatory process; the Company's ability to obtain additional financing to support the development and commercialization of HEPLISAV and its other operations, possible claims against the Company based on the patent rights of others; and other risks detailed in the "Risk Factors" section of our current periodic reports with the SEC. We undertake no obligation to revise or update information herein to reflect events or circumstances in the future, even if new information becomes available. Information on Dynavax's website at http://www.dynavax.com/ is not incorporated by reference in the Company's current periodic reports with the SEC.
Contact:
Michael Ostrach
Vice President and Chief Business Officer
510-665-7257
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BERKELEY, CA, Oct 04, 2010 (MARKETWIRE via COMTEX) -- In an abstract published today on the website of the 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD), Dynavax Technologies Corporation /quotes/comstock/15*!dvax/quotes/nls/dvax (DVAX 1.89, +0.03, +1.61%) reported that its novel hepatitis B vaccine candidate, HEPLISAV(TM), given as two doses over four weeks demonstrated superior seroprotection in persons with diabetes mellitus compared to Engerix-B given as three doses over 24 weeks. The subset analysis of 62 adults with diabetes in Dynavax's previously reported Phase 3 multicenter study (PHAST or Phase 3 HEPLISAV Short-regimen Trial), showed that at 12 weeks, 84 percent of adult diabetics treated with HEPLISAV achieved seroprotection as compared to 0 percent of adult diabetics treated with Engerix-B. At week 28, 93 percent of the HEPLISAV-treated group versus 35 percent in the Engerix-B group achieved seroprotection. HEPLISAV's significantly higher rate of seroprotection was achieved without further immunization past four weeks while the Engerix-B group received a third immunization at 24 weeks. A poster presentation (LB-17) entitled, "Immunogenicity of Two Doses of Investigational HEPLISAV(TM) Compared to Three Doses of Licensed Hepatitis B Vaccine (ENGERIX-B(R)) in Diabetics", will be made in a late-breaker session on November 1, 2010 at the AASLD in Boston, Massachusetts.
According to Dr. Tyler Martin, President and Chief Medical Officer of Dynavax, "Diabetics are at risk for hepatitis B infection, and once infected, their disease frequently results in more severe chronic illness. The situation is complicated by the fact that patients with diabetes commonly do not respond well to currently licensed hepatitis B vaccines. The data we will report at the AASLD meeting is particularly exciting as our technology clearly represents a potential breakthrough in immunization regimens as well as a means of significantly expanding the number of individuals for whom protection against hepatitis B will be possible.
"It is well known that epidemic outbreaks of hepatitis B have occurred over the last several years in long-term care facilities. However, vaccination against the disease has been limited because patients in this setting simply do not respond to vaccination as well as healthy, younger adults in the general population. The Center for Disease Control and Prevention's Advisory Committee on Immunization Practices (ACIP) has been studying the issue for quite some time, and later this month will consider a new recommendation for hepatitis B vaccination of adults with diabetes," Dr. Martin continued.
Dynavax first reported the results of its PHAST multi-center, observer-blinded Phase 3 study in August 2008. Of the 2101 subjects in the overall per protocol study population, the seroprotection rate of the HEPLISAV-treated group was 95 percent at week 12 and 81 percent at week 28 in the Engerix-B group, indicating non-inferiority/superiority of HEPLISAV over Engerix-B. HEPLISAV is Dynavax's novel hepatitis B vaccine candidate, a TLR9 agonist; Engerix-B is a commercially available hepatitis B vaccine.
Engerix-B(R) is a registered trademark of GlaxoSmithKline
About HEPLISAV
HEPLISAV is an investigational adult hepatitis B vaccine. The vaccine candidate is being evaluated in two Phase 3 studies that are directed toward fulfilling licensure requirements in U.S., Canada and Europe. In a completed pivotal Phase 3 trial, HEPLISAV demonstrated increased, rapid protection with fewer doses than current licensed vaccines. Dynavax has worldwide commercial rights to HEPLISAV and is developing the vaccine for large, high-value populations that are less responsive to current licensed vaccines, including individuals with chronic kidney disease. HEPLISAV combines hepatitis B surface antigen with a proprietary Toll-like Receptor 9 agonist known as ISS to enhance the immune response.
About Dynavax
Dynavax Technologies Corporation, a clinical-stage biopharmaceutical company, discovers and develops novel products to prevent and treat infectious diseases. The Company's lead product candidate is HEPLISAV, an investigational adult hepatitis B vaccine designed to enhance protection more rapidly and with fewer doses than current licensed vaccines. For more information visit http://www.dynavax.com/.
Forward Looking Statements
This press release contains "forward-looking statements," including the potential for use of HEPLISAV that are subject to a number of risks and uncertainties. Actual results may differ materially from those set forth in this press release due to the risks and uncertainties inherent in our business, including whether the reported results can be replicated in prospective studies, whether successful clinical and regulatory development and approval of HEPLISAV can occur in a timely manner or without significant additional studies or difficulties or delays in development or clinical trial enrollment, whether the studies can support registration for commercialization of HEPLISAV; the results of clinical trials and the impact of those results on the initiation and completion of subsequent trials and issues arising in the regulatory process; the Company's ability to obtain additional financing to support the development and commercialization of HEPLISAV and its other operations, possible claims against the Company based on the patent rights of others; and other risks detailed in the "Risk Factors" section of our current periodic reports with the SEC. We undertake no obligation to revise or update information herein to reflect events or circumstances in the future, even if new information becomes available. Information on Dynavax's website at http://www.dynavax.com/ is not incorporated by reference in the Company's current periodic reports with the SEC.
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510-665-7257
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October 3, 2010
New research reveals possible method for boosting the immune system to protect infants against HIV
October 3, 2010
- Researchers at Oregon Health &Science University may have uncovered a new weapon for combating HIV as it is passed from mother to newborn child. The research, which was led by researchers at OHSU's Oregon National Primate Research Center, will be published in the October 3rd online edition of the journal Nature Medicine.
"Mother-to-infant transmission of HIV is a tremendous worldwide problem, especially in several African nations," said Nancy Haigwood, Ph.D., researcher and director of the Oregon National Primate Research Center at OHSU.
According to the latest data from the World Health Organization, 33.4 million people were infected by the virus in 2008. About 67 percent of the world's infections are in African countries. In addition, 91 percent of the world's childhood infections are in Africa.
Haigwood, her colleagues at OHSU, along with researchers at the University of Washington are investigating strategies for preventing or countering HIV infections in babies born to women with HIV. Their strategy: to educate part of the baby's immune system within the first few hours of birth to better fight of the disease.
"HIV attacks and kills T-cells, the white blood cells that play an important role in the immune system because they have the ability to identify and destroy disease invaders. By attacking the body's natural defenses, the disease progresses, causes AIDS and eventually death," explained Haigwood. "Therefore, many therapies focus on protecting T-cells."
However, Haigwood and her colleagues took a different approach. They focused on another component of the immune system, which was initially thought to play a lesser role in the body's defense against HIV. Babies born to HIV-infected mothers have HIV-specific neutralizing antibodies at the time of birth that are "passively" acquired across the placenta. They wanted to determine whether boosted neutralizing antibody levels would weaken the disease's ability to overtake the body's defenses.
To investigate this possible treatment, the researchers studied three small groups of infant monkeys. The first group was given additional antibodies derived from healthy mothers. The second group was given antibodies matched to simian/human immunodeficiency virus (SHIV). SHIV is a hybrid virus used in research to ensure that results translate between species. The third group of animals was provided with HIV antibodies similar to, but not exactly matching, the strain of infection they would receive. The three groups were then exposed to SHIV and their immune systems were subsequently monitored.
Unlike the other two groups, the "HIV-matched" animals were better protected from the virus. They developed higher levels of neutralizing antibodies and, had lower levels of SHIV in their blood plasma than the comparison groups six months post-infection. In addition they maintained their CD4+ T cells - another component of the immune system.
The study also provided insights into the level of antibodies needed to impact disease progression. For this study, the antibody levels were relatively low dosed. Previously, antibodies were shown to block infection in animal models. This study demonstrated, for the first time, that very low levels of antibodies -- too low to block infection -- can influence disease progression in this setting and stimulate an immune response that contributes to viral control in the absence of drug treatment.
In future studies, the researchers hope to learn whether higher doses of antibodies translate into greater protection for the infants.
"This research demonstrates that boosting the body's HIV antibodies -- by a time-honored method of passive transfer that would use new HIV-specific human monoclonal antibodies -- may be a strategy for reducing infection levels and protecting CD4+ T cells in newborn children," said Haigwood. "While the treatment would not likely prevent infection, it could limit the levels of infection in children which would greatly reduce suffering and extend lives."
Provided by Oregon Health & Science University
Source
- Researchers at Oregon Health &Science University may have uncovered a new weapon for combating HIV as it is passed from mother to newborn child. The research, which was led by researchers at OHSU's Oregon National Primate Research Center, will be published in the October 3rd online edition of the journal Nature Medicine.
"Mother-to-infant transmission of HIV is a tremendous worldwide problem, especially in several African nations," said Nancy Haigwood, Ph.D., researcher and director of the Oregon National Primate Research Center at OHSU.
According to the latest data from the World Health Organization, 33.4 million people were infected by the virus in 2008. About 67 percent of the world's infections are in African countries. In addition, 91 percent of the world's childhood infections are in Africa.
Haigwood, her colleagues at OHSU, along with researchers at the University of Washington are investigating strategies for preventing or countering HIV infections in babies born to women with HIV. Their strategy: to educate part of the baby's immune system within the first few hours of birth to better fight of the disease.
"HIV attacks and kills T-cells, the white blood cells that play an important role in the immune system because they have the ability to identify and destroy disease invaders. By attacking the body's natural defenses, the disease progresses, causes AIDS and eventually death," explained Haigwood. "Therefore, many therapies focus on protecting T-cells."
However, Haigwood and her colleagues took a different approach. They focused on another component of the immune system, which was initially thought to play a lesser role in the body's defense against HIV. Babies born to HIV-infected mothers have HIV-specific neutralizing antibodies at the time of birth that are "passively" acquired across the placenta. They wanted to determine whether boosted neutralizing antibody levels would weaken the disease's ability to overtake the body's defenses.
To investigate this possible treatment, the researchers studied three small groups of infant monkeys. The first group was given additional antibodies derived from healthy mothers. The second group was given antibodies matched to simian/human immunodeficiency virus (SHIV). SHIV is a hybrid virus used in research to ensure that results translate between species. The third group of animals was provided with HIV antibodies similar to, but not exactly matching, the strain of infection they would receive. The three groups were then exposed to SHIV and their immune systems were subsequently monitored.
Unlike the other two groups, the "HIV-matched" animals were better protected from the virus. They developed higher levels of neutralizing antibodies and, had lower levels of SHIV in their blood plasma than the comparison groups six months post-infection. In addition they maintained their CD4+ T cells - another component of the immune system.
The study also provided insights into the level of antibodies needed to impact disease progression. For this study, the antibody levels were relatively low dosed. Previously, antibodies were shown to block infection in animal models. This study demonstrated, for the first time, that very low levels of antibodies -- too low to block infection -- can influence disease progression in this setting and stimulate an immune response that contributes to viral control in the absence of drug treatment.
In future studies, the researchers hope to learn whether higher doses of antibodies translate into greater protection for the infants.
"This research demonstrates that boosting the body's HIV antibodies -- by a time-honored method of passive transfer that would use new HIV-specific human monoclonal antibodies -- may be a strategy for reducing infection levels and protecting CD4+ T cells in newborn children," said Haigwood. "While the treatment would not likely prevent infection, it could limit the levels of infection in children which would greatly reduce suffering and extend lives."
Provided by Oregon Health & Science University
Source
New HCV Antivirals and Drug Resistance
Alan Franciscus, Editor-in-Chief
Lucinda K. Porter, RN
HCV Advocate
Researchers are investigating new antiviral medications to treat hepatitis C virus infection (HCV). Some of these drugs are referred to as direct antiviral medications since they specifically target the hepatitis C virus. However, unlike current HCV medications, direct antivirals carry the potential for resistance. This fact sheet will discuss the basics of HCV replication and why the hepatitis C virus becomes resistant to the newer drugs.
The Basics
Viruses are like rabbits; what they do best is multiply. The term for this is viral replication. However, a virus cannot survive on its own; it can only survive inside of another living cell, known as a host cell. Viruses use various pieces of the host cell’s genetic material in order to reproduce, or make more copies of itself. Viruses survive because of their ability to constantly adapt and change when they are under attack from the immune system. Viruses still try to reproduce even while under attack. In a hurry to escape, a virus may make a bad copy of itself, which slightly alters its genetic make-up. The process of change actually produces a variation in the virus, known as a mutation or quasi-species.
HCV acts like this. When you are newly infected, your immune system recognizes that an uninvited intruder (HCV) is in your body. Your immune system alerts your body to destroy HCV. However, HCV hurries to escape and makes a sloppy copy of itself, which outwits your immune system. Your immune system is patrolling for the original intruder, not realizing that the virus now looks a bit different. Now HCV can multiply at a faster rate. Eventually your immune system catches on and looks for the bad copy. In a hurry, HCV mutates again. This process may cycle through many, many mutations.
One way to think about this is with Darwin’s theory of evolution and survival of the fittest. In nature, the strong survive. The weak die and if they die before they reproduce, their weak genetic material dies too. In this way, it is more likely that strong genetic material is passed along. Evolution applies to plants, animals and microorganisms.
Current Therapies
The current standard of care for treating hepatitis C is a combination of pegylated interferon (long-acting) plus ribavirin therapy. How pegylated interferon works is not completely understood. What is known is this: 1) interferon boosts the ability of the body’s immune system to kill a virus, and 2) it protects noninfected cells from becoming infected. Interferon is used to treat a variety of diseases including hepatitis C.
We also do not understand how ribavirin works against HCV, but, when used with interferon, it seems to interfere with HCV’s ability to multiply, or replicate. Ribavirin alone is not effective against hepatitis C. When interferon and ribavirin are combined, there is a synergistic effect, which eliminates HCV in about half the people who take this combination. Synergy means that the combined total is greater than the sum of the separate parts.
Drug resistance does not develop with interferon and ribavirin since these drugs do not specifically target the enzymes of the virus used in the viral replication process. This means that treatment durations may vary in length and be tailored to patients’ needs. Patients may also undergo multiple treatments using the same drug(s). It is also the reason why people may interrupt or stop therapy without the development of drug resistance.
The HCV Replication Process and Direct Antivirals
The hepatitis C virus is a single-stranded RNA virus of the flavivirus family with a very rapid turnover or replication rate. HCV enters the body and targets the liver – the main replication site of HCV. The virus attaches itself to the outer coating of the liver cell or hepatocyte, and enters the cell. After entering the cell, HCV releases its genetic material and hijacks the cell’s internal processes.
Now that HCV has taken over, it binds to various ribosome sites within the cell. A ribosome is like a factory with printing presses. If a master copy of a document has a mistake in it, all of the copies will have that same mistake. This is referred to as translation. Drugs are being developed to interfere with this process, but so far, none have been found to be effective in stopping the translation process.
The next step involves an enzyme called the protease. HCV genetic material uses the protease enzyme to ‘cut up’ the genetic material into smaller pieces before additional viral processing. If this process is inter rupted, then the virus cannot make copies of itself. Protease inhibitors are exciting prospects in drug development to treat HCV since there are many potential protease enzymes involved in the replication process of the hepatitis C virus. The drugs in human clinical trial development that look the most promising are telaprevir and boceprevir.
Other materials that viruses depend on for replication are polymerase enzymes. HCV cannot multiply without these enzymes. Polymerase inhibitors are drugs used to stop this process . HCV polymerase inhibitors in human clinical trials include ABT-450 HCV, R7128, and PSI-938.
Viral replication relies on the helicase enzyme to complete the process. There are no HCV helicase inhibitors currently in development. Most experts believe that it will be difficult, if not impossible, to develop helicase inhibitors.
Resistance and Direct Antivirals
The new direct antivirals work by inhibiting the entry of the virus or by inhibiting the specific enzymes during one of the replication processes. The medications that look the most promising are the HCV protease and polymerase inhibitors. During the normal lifecycle of HCV, the body’s immune system exerts pressure on the replicating virus. This pressure produces mutations that escape the host’s immune response.
In a similar way, drugs to treat hepatitis C will exert pressure on the virus to change and mutate in order to survive. For this reason, it is believed that most of the direct antiviral medications will eventually produce drug resistant mutations, especially if these drugs are taken for a long time. This in turn may make the new medications ineffective in treating the new viral mutations.
Drug resistance is expected. However, scientists are looking for ways to prevent or interfere with drug resistance. For instance, drug resistant mutations may be identified earlier in the process, such as during the test tube development phase.
Preventing and Reducing Drug Resistance
The reduction or prevention of drug resistance depends on a number of factors. Some of these are:
Eradicating HCV: Unlike HIV and HBV, hepatitis C does not become part of the host cell. We have been able to rid HCV from the body with the use of current medications – pegylated interferon and ribavirin. In addition, HCV is an RNA virus. Since it does not integrate into the host cell’s DNA, as mentioned above, it will be easier to eliminate HCV without the risk of the virus changing or mutating.
Combination of direct and indirect antivirals: Direct antivirals can be given for a shorter period of time – this reduces the chances for the virus to ‘resist’ the drug. When used in combination with indirect antivirals – peginterferon and/or ribavirin, the chances of the virus developing resistance to the drug is lower. An example of this is extending the duration of treatment with peginterferon and/or ribavirin after stopping the direct HCV antiviral. This may prevent drug resistance while allowing for continual and hopefully complete viral suppression. For instance, telaprevir and boceprevir used in combination with pegylated interferon plus ribavirin have completed their phase III studies for people who have never been treated. It was found that treatment duration could be reduced for some people who responded to the new medications early on in treatment and that the total treatment duration could be reduced from 48 weeks to 24 or 36 weeks.
Potent direct antivirals: The development of potent direct antivirals that quickly distribute throughout the body and reach high blood concentrations in a short time period will put enough pressure on the virus before it has a chance to mutate. If the drugs are not potent enough, the escaped viral mutations may become the dominant virus, rendering the antiviral medication ineffective.
Combination direct antivirals: The use of direct antivirals that inhibit several different protease and/or polymerase enzymes at the same time will reduce the ability of the virus to mutate.
Adherence: Current HCV medications require adherence to prescribed doses and durations to be more effective in treating HCV. The new direct antivirals will require strict adherence. Doses that are skipped or forgotten could lead to viral mutations and drug resistance.
HCV research has benefited from what we know about HIV and HBV drug resistance and hopefully will be able to contribute to this body of knowledge. As we begin this era of new HCV medications, now is the right time to develop strategies to make HCV therapy more effective. Now is also the time to reduce the chances of the surfacing of drug resistance that could potentially reverse some of the benefits of new therapies. The best strategy for moving forward depends on using knowledge from the past in order to discover the future.
For more information about drugs in development to treat hepatitis C, visit our HCV Drug pipeline. www.hcvadvocate.org/hepatitis/hepC/HCVDrugs.html
For information about current clinical trial enrollment visit: http://www.clinicaltrials.gov/
Source
Lucinda K. Porter, RN
HCV Advocate
Researchers are investigating new antiviral medications to treat hepatitis C virus infection (HCV). Some of these drugs are referred to as direct antiviral medications since they specifically target the hepatitis C virus. However, unlike current HCV medications, direct antivirals carry the potential for resistance. This fact sheet will discuss the basics of HCV replication and why the hepatitis C virus becomes resistant to the newer drugs.
The Basics
Viruses are like rabbits; what they do best is multiply. The term for this is viral replication. However, a virus cannot survive on its own; it can only survive inside of another living cell, known as a host cell. Viruses use various pieces of the host cell’s genetic material in order to reproduce, or make more copies of itself. Viruses survive because of their ability to constantly adapt and change when they are under attack from the immune system. Viruses still try to reproduce even while under attack. In a hurry to escape, a virus may make a bad copy of itself, which slightly alters its genetic make-up. The process of change actually produces a variation in the virus, known as a mutation or quasi-species.
HCV acts like this. When you are newly infected, your immune system recognizes that an uninvited intruder (HCV) is in your body. Your immune system alerts your body to destroy HCV. However, HCV hurries to escape and makes a sloppy copy of itself, which outwits your immune system. Your immune system is patrolling for the original intruder, not realizing that the virus now looks a bit different. Now HCV can multiply at a faster rate. Eventually your immune system catches on and looks for the bad copy. In a hurry, HCV mutates again. This process may cycle through many, many mutations.
One way to think about this is with Darwin’s theory of evolution and survival of the fittest. In nature, the strong survive. The weak die and if they die before they reproduce, their weak genetic material dies too. In this way, it is more likely that strong genetic material is passed along. Evolution applies to plants, animals and microorganisms.
Current Therapies
The current standard of care for treating hepatitis C is a combination of pegylated interferon (long-acting) plus ribavirin therapy. How pegylated interferon works is not completely understood. What is known is this: 1) interferon boosts the ability of the body’s immune system to kill a virus, and 2) it protects noninfected cells from becoming infected. Interferon is used to treat a variety of diseases including hepatitis C.
We also do not understand how ribavirin works against HCV, but, when used with interferon, it seems to interfere with HCV’s ability to multiply, or replicate. Ribavirin alone is not effective against hepatitis C. When interferon and ribavirin are combined, there is a synergistic effect, which eliminates HCV in about half the people who take this combination. Synergy means that the combined total is greater than the sum of the separate parts.
Drug resistance does not develop with interferon and ribavirin since these drugs do not specifically target the enzymes of the virus used in the viral replication process. This means that treatment durations may vary in length and be tailored to patients’ needs. Patients may also undergo multiple treatments using the same drug(s). It is also the reason why people may interrupt or stop therapy without the development of drug resistance.
The HCV Replication Process and Direct Antivirals
The hepatitis C virus is a single-stranded RNA virus of the flavivirus family with a very rapid turnover or replication rate. HCV enters the body and targets the liver – the main replication site of HCV. The virus attaches itself to the outer coating of the liver cell or hepatocyte, and enters the cell. After entering the cell, HCV releases its genetic material and hijacks the cell’s internal processes.
Now that HCV has taken over, it binds to various ribosome sites within the cell. A ribosome is like a factory with printing presses. If a master copy of a document has a mistake in it, all of the copies will have that same mistake. This is referred to as translation. Drugs are being developed to interfere with this process, but so far, none have been found to be effective in stopping the translation process.
The next step involves an enzyme called the protease. HCV genetic material uses the protease enzyme to ‘cut up’ the genetic material into smaller pieces before additional viral processing. If this process is inter rupted, then the virus cannot make copies of itself. Protease inhibitors are exciting prospects in drug development to treat HCV since there are many potential protease enzymes involved in the replication process of the hepatitis C virus. The drugs in human clinical trial development that look the most promising are telaprevir and boceprevir.
Other materials that viruses depend on for replication are polymerase enzymes. HCV cannot multiply without these enzymes. Polymerase inhibitors are drugs used to stop this process . HCV polymerase inhibitors in human clinical trials include ABT-450 HCV, R7128, and PSI-938.
Viral replication relies on the helicase enzyme to complete the process. There are no HCV helicase inhibitors currently in development. Most experts believe that it will be difficult, if not impossible, to develop helicase inhibitors.
Resistance and Direct Antivirals
The new direct antivirals work by inhibiting the entry of the virus or by inhibiting the specific enzymes during one of the replication processes. The medications that look the most promising are the HCV protease and polymerase inhibitors. During the normal lifecycle of HCV, the body’s immune system exerts pressure on the replicating virus. This pressure produces mutations that escape the host’s immune response.
In a similar way, drugs to treat hepatitis C will exert pressure on the virus to change and mutate in order to survive. For this reason, it is believed that most of the direct antiviral medications will eventually produce drug resistant mutations, especially if these drugs are taken for a long time. This in turn may make the new medications ineffective in treating the new viral mutations.
Drug resistance is expected. However, scientists are looking for ways to prevent or interfere with drug resistance. For instance, drug resistant mutations may be identified earlier in the process, such as during the test tube development phase.
Preventing and Reducing Drug Resistance
The reduction or prevention of drug resistance depends on a number of factors. Some of these are:
Eradicating HCV: Unlike HIV and HBV, hepatitis C does not become part of the host cell. We have been able to rid HCV from the body with the use of current medications – pegylated interferon and ribavirin. In addition, HCV is an RNA virus. Since it does not integrate into the host cell’s DNA, as mentioned above, it will be easier to eliminate HCV without the risk of the virus changing or mutating.
Combination of direct and indirect antivirals: Direct antivirals can be given for a shorter period of time – this reduces the chances for the virus to ‘resist’ the drug. When used in combination with indirect antivirals – peginterferon and/or ribavirin, the chances of the virus developing resistance to the drug is lower. An example of this is extending the duration of treatment with peginterferon and/or ribavirin after stopping the direct HCV antiviral. This may prevent drug resistance while allowing for continual and hopefully complete viral suppression. For instance, telaprevir and boceprevir used in combination with pegylated interferon plus ribavirin have completed their phase III studies for people who have never been treated. It was found that treatment duration could be reduced for some people who responded to the new medications early on in treatment and that the total treatment duration could be reduced from 48 weeks to 24 or 36 weeks.
Potent direct antivirals: The development of potent direct antivirals that quickly distribute throughout the body and reach high blood concentrations in a short time period will put enough pressure on the virus before it has a chance to mutate. If the drugs are not potent enough, the escaped viral mutations may become the dominant virus, rendering the antiviral medication ineffective.
Combination direct antivirals: The use of direct antivirals that inhibit several different protease and/or polymerase enzymes at the same time will reduce the ability of the virus to mutate.
Adherence: Current HCV medications require adherence to prescribed doses and durations to be more effective in treating HCV. The new direct antivirals will require strict adherence. Doses that are skipped or forgotten could lead to viral mutations and drug resistance.
HCV research has benefited from what we know about HIV and HBV drug resistance and hopefully will be able to contribute to this body of knowledge. As we begin this era of new HCV medications, now is the right time to develop strategies to make HCV therapy more effective. Now is also the time to reduce the chances of the surfacing of drug resistance that could potentially reverse some of the benefits of new therapies. The best strategy for moving forward depends on using knowledge from the past in order to discover the future.
For more information about drugs in development to treat hepatitis C, visit our HCV Drug pipeline. www.hcvadvocate.org/hepatitis/hepC/HCVDrugs.html
For information about current clinical trial enrollment visit: http://www.clinicaltrials.gov/
Source
Interferon- Vs. Non-Interferon-Based Therapy for Chronic Hepatitis B: Appropriate Patient Selection Is Key
One of the fundamental lessons we learn as medical providers is that the effectiveness and safety of drugs often vary between patients. Accordingly, patient selection may be key for making the best treatment decision. The stakes are even higher when drugs with predictable adverse effects are considered. All of these issues assume center stage when determining the type of antiviral therapy to treat hepatitis B.
Tolerability of antiviral therapy
Interferon accounts for no more than 10 percent of prescriptions for antiviral therapy in Europe and North America.1 The major reason for this is the inherently safer profile for nucleoside analogues and the need for less complex monitoring. It should be noted, however, that interferon-treated hepatitis B patients have better quality of life and improved tolerability than similarly treated patients with hepatitis C.2
Unfortunately, better patient acceptance with nucleoside analogues does not necessarily ensure better compliance, because as many as 30 percent of patients are not compliant with maintenance nucleoside analogue therapy.
Interferon is always contraindicated in patients with any level of liver decompensation due to flares of hepatitis and risk for serious infection. Practical experience indicates that interferon is less well tolerated in patients over the age of 60 and in those with significant co-morbid illnesses.
Differences in virologic response
Loss of hepatitis B surface antigen (HBsAg) is an important event, leading to improved outcomes and reduced rates of long-term complications.3 It is the closest one that comes to a clinical cure in hepatitis B.
Studies with standard or pegylated interferon have shown that 24 to 48 weeks of treatment accelerates the time to HBsAg loss. This occurs in a small number (3 percent to 5 percent) of hepatitis B cases initially, but prolonged follow-up demonstrates further gains in HBsAg clearance as long as durable hepatitis B virus (HBV) DNA suppression is maintained after treatment.4,5 By contrast, loss of HBsAg rarely occurs with nucleoside analogues, even with several years of therapy. Recent experience with tenofovir challenges this concept, but unlike the situation with interferon, HBsAg clearance has thus far been confined to non-Asians with hepatitis B virus e antigen (HBeAg)-positive hepatitis B. The reasons for the different kinetics of HBsAg clearance with the two classes of drug are not well understood, but the immunomodulatory effect of interferon is likely to play an important role.
The low rate of initial HBsAg clearance with both interferon and nucleoside analogue therapy has led to the use of “intermediate” efficacy endpoints such as sustained lowering of HBV DNA and HBeAg seroconversion. While “comparable” efficacy rates have been claimed, clinical extension trials of nucleoside analogues demonstrate that several years of treatment generally elapse before the rate of HBeAg seroconversion is equivalent (~30 percent) to that observed with interferon.
Patient selection
The efficacy of interferon, however, is very modest in HBeAg-positive cases with low alanine transaminase (ALT) (less than two times ULN) and high HBV DNA levels (greater than 200 million mIU/mL). In such cases, nucleoside analogue therapy is advisable. In my experience, it is also reasonable to use nucleoside analogue therapy as first-line treatment when baseline ALT is greater than or equal to five times ULN because this predicts a greater than 50 percent rate of HBeAg loss with one year of treatment.
Viral genotype is an especially important feature in determining the likelihood of response to interferon in HBeAg-positive hepatitis. Genotype A and B patients respond best and are more likely to lose not only HBeAg, but HBsAg. A treatment algorithm has recently been published by Janssen et al. that is based on the relationship between baseline patient features, viral genotype and the rate of HBeAg loss in a large number of pegylated interferon-treated cases.6 The accompanying table indicates what I have found to be the most important factors in my day-to-day experience.
Unfortunately, there are no clear-cut predictors of response in HBeAg-negative hepatitis B, a condition where relapse is frequent with 48 weeks of interferon or several years of nucleoside analogue therapy. The relationship between durable HBV DNA suppression off therapy and viral genotype is less well understood, but some studies have demonstrated that genotype D patients are especially difficult to treat. Ironically, HBsAg clearance has been demonstrated to occur in genotype D patients treated with pegylated interferon.6
Combination antiviral therapy
We do not know if pegylated interferon combined with newer nucleoside analogues such as entecavir or tenofovir results in a higher rate of durable viral suppression, HBeAg clearance or HBsAg clearance. Preliminary studies have suggested enhanced efficacy compared to previous studies using lamivudine. This may be due to the lower rates of resistance associated with newer agents. Ongoing treatment trials in HBeAg-positive and -negative hepatitis B, including one sponsored by the NIH (Hepatitis B Research Network, http://www.hepbnet.org/), will address this more definitively. Should significantly higher rates of response be found with combination therapy, it will be important to determine the baseline characteristics that predict a higher rate of response compared to either drug alone. Thus, patient selection is likely to remain key in the future as well, as better therapies are demonstrated. For me, hepatitis B is a condition where the old adage of “one size fits all” is likely to never apply.
References
1.Perrillo R. Benefits and risks of interferon therapy for hepatitis B. Hepatology 2009; 49:S103-11.
2.Marcellin P, Lau GK, Zeuzem S, et al. Comparing the safety, tolerability, and quality of life in patients with chronic hepatitis B vs chronic hepatitis C treated with peginterferon alfa-2a. Liver Int 2008; 28:477-85.
3.Fattovich G, Giustina G, Sanchez-Tapias J, et al. Delayed clearance of serum HbsAg in compensated cirrhosis B: relation to interferon alpha therapy and disease prognosis. European Concerted Action on Viral Hepatitis (EUROHEP). Am J Gastroenterol 1998; 93:896-900.
4.Buster EH, Flink HJ, Cakaloglu Y, et al. Sustained HBeAg and HBsAg loss after long-term follow-up of HBeAg-positive patients treated with peginterferon alpha-2b. Gastroenterology 2008; 135:459-67.
5.Marcellin P, Bonino F, Lau GK, et al. Sustained response of hepatitis B e antigen-negative patients 3 years after treatment with peginterferon alpha-2. Gastroenterology 2009; 136:2169-79.
6.Buster EH, Hansen BE, Lau GK, et al. Factors that predict response of patients with hepatitis B e antigen-positive chronic hepatitis B to peginterferon alfa. Gastroenterology 2009; 137:2002-9.
Source
Achillion to Present Multiple Posters at AASLD's The Liver Meeting 2010
ACH-1625 Protease Inhibitor Abstract Accepted as Late Breaking Poster
Growing Data Set Underscores Company's Significant HCV Franchise
NEW HAVEN, Conn., Sept. 15, 2010 (GLOBE NEWSWIRE) -- Achillion Pharmaceuticals, Inc. /quotes/comstock/15*!achn/quotes/nls/achn (ACHN 2.96, -0.06, -1.99%) , a leader in the discovery and development of treatments for the most challenging infectious diseases, today announced that its abstract titled "ACH-1625 Demonstrates Sustained Viral Suppression in Presence of Uncommon Drug Resistant HCV Variants: Pharmacokinetic, Pharmacodynamic and Clinical Virology Analysis of Phase I Study" has been accepted as a late breaking poster presentation at the 61st Annual Meeting of the American Association for the Study of Liver Disease (AASLD) The Liver Meeting(R) 2010 being held October 29-November 2, 2010 in Boston.
Two additional abstracts on ACH-1625 titled "In Vitro Combination Studies of ACH-1625 (HCV NS3 Protease Inhibitor) and ACH-2928 (HCV NS5A inhibitor) in Presence and Absence of Ribavirin" and "Non-Clinical Studies to Assess Drug-Drug Interaction Potential of ACH-1625, a Clinically Effective HCV NS3 Protease Inhibitor" had previously been accepted for poster presentation.
In addition, an abstract on ACH-2684 titled "HCV NS3 Protease Inhibitor with Potent Activity against Multiple Genotypes and Known Resistant Variants" was previously accepted for poster presentation.
Achillion's late breaking poster will be displayed in the Late Breaking Poster Session on Monday, November 1 at 8:00 a.m. through the end of the day's session. The balance of the Company's posters will be displayed in the HCV Therapy: Preclinical and Early Clinical Development Poster Session on Tuesday, November 2 at 7:00 a.m. through the end of the day's session.
"The Liver Meeting 2010 is noteworthy for Achillion because, for the first time, we are presenting a significant amount of clinical data in support of our expanding HCV pipeline of products. The clinical data for ACH-1625 further supports this compound's potential to be a best-in-class therapy, and our pre-clinical data elucidate the potential for powerful combination therapies with our own drug candidates," noted Michael Kishbauch, President and Chief Executive Officer
"We were especially pleased to have our data selected for a Late Breaking poster as it underscores the importance of our positive clinical data with ACH-1625 to treat HCV since only a few such submissions were chosen for Late Breaking presentation. We look forward to sharing our positive results with the clinical and scientific audience at AASLD and to advancing ACH-1625 into Phase 2 studies this month."
About American Association for the Study of Liver Diseases
AASLD is the leading organization of scientists and healthcare professionals committed to preventing and curing liver disease. AASLD was founded in 1950 by a small group of leading liver specialists to bring together those who had contributed to the field of hepatology.
AASLD has grown to an international society responsible for all aspects of hepatology, and its annual meeting, The Liver Meeting(R), has grown in attendance from 12 to over 7,000 physicians, surgeons, researchers, and allied health professionals from around the world.
Hepatology has been recognized as a discipline only in the last few decades, and AASLD played a seminal and unifying role in focusing interest on hepatological problems, as well as the founding of other hepatological societies. AASLD organized the American Liver Foundation to educate the public about liver diseases.
About ACH-1625
ACH-1625 is an HCV protease inhibitor designed and synthesized based on crystal structures of enzyme/inhibitor complex. ACH-1625 is an open chain, non-covalent, reversible inhibitor of NS3 protease. In preclinical studies, ACH-1625 demonstrated high potency, unique pharmacokinetic properties and an excellent safety profile at high drug exposures. With its rapid and extensive partitioning to the liver, as well as high liver/plasma ratios demonstrated in preclinical studies, Achillion believes that ACH-1625 has the potential for once daily dosing. ACH-1625 has shown low single-digit nanomolar potency that is specific to HCV. It is equipotent against HCV genotypes 1a and 1b at IC50~1nM.
In clinical studies completed to date, subjects receiving both single and multiple ascending doses ranging from 50 mg to 2000 mg for periods up to 5 days demonstrated that ACH-1625 was well tolerated at all doses and there were no serious adverse events, no clinically significant changes in vital signs, electrocardiograms (ECGs), or laboratory evaluations. HCV-infected patients receiving doses ranging from 200 to 600 mg twice daily, and 400 to 600 mg once daily, showed mean maximal reductions in viral load ranging from of 3.81og10 to 4.25 log10. Furthermore, all patients had viral loads that remained suppressed for at least 7 days after dosing was completed, maintaining a mean reduction of more than 2.0log10 from baseline through day 12, the last day of viral load measurement in the study.
About ACH-2684
ACH-2684 is a high potency protease inhibitor with potency in the picomolar range and activity against all HCV genotypes including highly-resistant strains of the HCV virus. The potency and virology profile of ACH-2684 demonstrates that it very effectively suppresses a broad range of natural variants of the hepatitis C virus, and may be effective in prevention and treatment of emerging resistant variants. This compound also retains potent activity against all genotypes.
About ACH-2928
ACH-2928, an NS5A inhibitor with potent activity against all genotypes, is highly effective in combination with NS3 protease inhibitors, NS5B polymerase inhibitors, interferon and ribavirin. In preclinical studies ACH-2928 has demonstrated excellent potency against HCV RNA replication, as well as good pharmacokinetic and safety profiles.
About Achillion
Achillion is an innovative pharmaceutical company dedicated to bringing important new treatments to patients with infectious disease. Achillion's proven discovery and development teams have advanced multiple product candidates with novel mechanisms of action. Achillion is focused on solutions for the most challenging problems in infectious disease -- hepatitis C, resistant bacterial infections and HIV. For more information on Achillion Pharmaceuticals, please visit www.achillion.com or call 1-203-624-7000.
This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including statements with respect to the potency, safety and other characteristics of ACH-1625, which may not be duplicated in future cohorts at different doses or in future clinical studies of longer duration; Achillion's expectations regarding timing and duration of other clinical trials, including additional dosing cohorts. Among the factors that could cause actual results to differ materially from those indicated by such forward-looking statements are uncertainties relating to results of clinical trials and unexpected regulatory actions or delays. These and other risks are described in the reports filed by Achillion with the U.S. Securities and Exchange Commission, including its Annual Report on Form 10-K for the fiscal year ended December 31, 2009.
All forward-looking statements reflect Achillion's expectations only as of the date of this release and should not be relied upon as reflecting Achillion's views, expectations or beliefs at any date subsequent to the date of this release. Achillion anticipates that subsequent events and developments may cause these views, expectations and beliefs to change. However, while Achillion may elect to update these forward-looking statements at some point in the future, it specifically disclaims any obligation to do so.
This news release was distributed by GlobeNewswire, http://www.globenewswire.com/
SOURCE: Achillion Pharmaceuticals, Inc.
CONTACT: Achillion Pharmaceuticals, Inc.
Mary Kay Fenton
(203) 624-7000
mfenton@achillion.com
Lippert/Heilshorn & Associates, Inc.
Investors:
Anne Marie Fields
(212) 838-3777
afields@lhai.com
Bruce Voss
(310) 691-7100
bvoss@lhai.com
Source
Growing Data Set Underscores Company's Significant HCV Franchise
NEW HAVEN, Conn., Sept. 15, 2010 (GLOBE NEWSWIRE) -- Achillion Pharmaceuticals, Inc. /quotes/comstock/15*!achn/quotes/nls/achn (ACHN 2.96, -0.06, -1.99%) , a leader in the discovery and development of treatments for the most challenging infectious diseases, today announced that its abstract titled "ACH-1625 Demonstrates Sustained Viral Suppression in Presence of Uncommon Drug Resistant HCV Variants: Pharmacokinetic, Pharmacodynamic and Clinical Virology Analysis of Phase I Study" has been accepted as a late breaking poster presentation at the 61st Annual Meeting of the American Association for the Study of Liver Disease (AASLD) The Liver Meeting(R) 2010 being held October 29-November 2, 2010 in Boston.
Two additional abstracts on ACH-1625 titled "In Vitro Combination Studies of ACH-1625 (HCV NS3 Protease Inhibitor) and ACH-2928 (HCV NS5A inhibitor) in Presence and Absence of Ribavirin" and "Non-Clinical Studies to Assess Drug-Drug Interaction Potential of ACH-1625, a Clinically Effective HCV NS3 Protease Inhibitor" had previously been accepted for poster presentation.
In addition, an abstract on ACH-2684 titled "HCV NS3 Protease Inhibitor with Potent Activity against Multiple Genotypes and Known Resistant Variants" was previously accepted for poster presentation.
Achillion's late breaking poster will be displayed in the Late Breaking Poster Session on Monday, November 1 at 8:00 a.m. through the end of the day's session. The balance of the Company's posters will be displayed in the HCV Therapy: Preclinical and Early Clinical Development Poster Session on Tuesday, November 2 at 7:00 a.m. through the end of the day's session.
"The Liver Meeting 2010 is noteworthy for Achillion because, for the first time, we are presenting a significant amount of clinical data in support of our expanding HCV pipeline of products. The clinical data for ACH-1625 further supports this compound's potential to be a best-in-class therapy, and our pre-clinical data elucidate the potential for powerful combination therapies with our own drug candidates," noted Michael Kishbauch, President and Chief Executive Officer
"We were especially pleased to have our data selected for a Late Breaking poster as it underscores the importance of our positive clinical data with ACH-1625 to treat HCV since only a few such submissions were chosen for Late Breaking presentation. We look forward to sharing our positive results with the clinical and scientific audience at AASLD and to advancing ACH-1625 into Phase 2 studies this month."
About American Association for the Study of Liver Diseases
AASLD is the leading organization of scientists and healthcare professionals committed to preventing and curing liver disease. AASLD was founded in 1950 by a small group of leading liver specialists to bring together those who had contributed to the field of hepatology.
AASLD has grown to an international society responsible for all aspects of hepatology, and its annual meeting, The Liver Meeting(R), has grown in attendance from 12 to over 7,000 physicians, surgeons, researchers, and allied health professionals from around the world.
Hepatology has been recognized as a discipline only in the last few decades, and AASLD played a seminal and unifying role in focusing interest on hepatological problems, as well as the founding of other hepatological societies. AASLD organized the American Liver Foundation to educate the public about liver diseases.
About ACH-1625
ACH-1625 is an HCV protease inhibitor designed and synthesized based on crystal structures of enzyme/inhibitor complex. ACH-1625 is an open chain, non-covalent, reversible inhibitor of NS3 protease. In preclinical studies, ACH-1625 demonstrated high potency, unique pharmacokinetic properties and an excellent safety profile at high drug exposures. With its rapid and extensive partitioning to the liver, as well as high liver/plasma ratios demonstrated in preclinical studies, Achillion believes that ACH-1625 has the potential for once daily dosing. ACH-1625 has shown low single-digit nanomolar potency that is specific to HCV. It is equipotent against HCV genotypes 1a and 1b at IC50~1nM.
In clinical studies completed to date, subjects receiving both single and multiple ascending doses ranging from 50 mg to 2000 mg for periods up to 5 days demonstrated that ACH-1625 was well tolerated at all doses and there were no serious adverse events, no clinically significant changes in vital signs, electrocardiograms (ECGs), or laboratory evaluations. HCV-infected patients receiving doses ranging from 200 to 600 mg twice daily, and 400 to 600 mg once daily, showed mean maximal reductions in viral load ranging from of 3.81og10 to 4.25 log10. Furthermore, all patients had viral loads that remained suppressed for at least 7 days after dosing was completed, maintaining a mean reduction of more than 2.0log10 from baseline through day 12, the last day of viral load measurement in the study.
About ACH-2684
ACH-2684 is a high potency protease inhibitor with potency in the picomolar range and activity against all HCV genotypes including highly-resistant strains of the HCV virus. The potency and virology profile of ACH-2684 demonstrates that it very effectively suppresses a broad range of natural variants of the hepatitis C virus, and may be effective in prevention and treatment of emerging resistant variants. This compound also retains potent activity against all genotypes.
About ACH-2928
ACH-2928, an NS5A inhibitor with potent activity against all genotypes, is highly effective in combination with NS3 protease inhibitors, NS5B polymerase inhibitors, interferon and ribavirin. In preclinical studies ACH-2928 has demonstrated excellent potency against HCV RNA replication, as well as good pharmacokinetic and safety profiles.
About Achillion
Achillion is an innovative pharmaceutical company dedicated to bringing important new treatments to patients with infectious disease. Achillion's proven discovery and development teams have advanced multiple product candidates with novel mechanisms of action. Achillion is focused on solutions for the most challenging problems in infectious disease -- hepatitis C, resistant bacterial infections and HIV. For more information on Achillion Pharmaceuticals, please visit www.achillion.com or call 1-203-624-7000.
This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including statements with respect to the potency, safety and other characteristics of ACH-1625, which may not be duplicated in future cohorts at different doses or in future clinical studies of longer duration; Achillion's expectations regarding timing and duration of other clinical trials, including additional dosing cohorts. Among the factors that could cause actual results to differ materially from those indicated by such forward-looking statements are uncertainties relating to results of clinical trials and unexpected regulatory actions or delays. These and other risks are described in the reports filed by Achillion with the U.S. Securities and Exchange Commission, including its Annual Report on Form 10-K for the fiscal year ended December 31, 2009.
All forward-looking statements reflect Achillion's expectations only as of the date of this release and should not be relied upon as reflecting Achillion's views, expectations or beliefs at any date subsequent to the date of this release. Achillion anticipates that subsequent events and developments may cause these views, expectations and beliefs to change. However, while Achillion may elect to update these forward-looking statements at some point in the future, it specifically disclaims any obligation to do so.
This news release was distributed by GlobeNewswire, http://www.globenewswire.com/
SOURCE: Achillion Pharmaceuticals, Inc.
CONTACT: Achillion Pharmaceuticals, Inc.
Mary Kay Fenton
(203) 624-7000
mfenton@achillion.com
Lippert/Heilshorn & Associates, Inc.
Investors:
Anne Marie Fields
(212) 838-3777
afields@lhai.com
Bruce Voss
(310) 691-7100
bvoss@lhai.com
Source
October 2, 2010
Prevalence and characteristics of hepatitis B and C virus infections in treatment-naïve HIV-infected patients
Medical Microbiology and Immunology
DOI: 10.1007/s00430-010-0172-zOnline First™
Original Investigation
Stefan Reuter, Mark Oette, Frank Clemens Wilhelm, Bastian Beggel, Rolf Kaiser, Melanie Balduin, Finja Schweitzer, Jens Verheyen, Ortwin Adams and Thomas Lengauer, et al.
Abstract
In HIV-infected treatment-naïve patients, we analyzed risk factors for either chronic hepatitis B (HBV) infection, occult HBV infection (OHBV) or a positive hepatitis C (HCV) serostatus. A total of 918 patients of the RESINA-cohort in Germany were included in this study. Before initiating antiretroviral therapy, clinical parameters were collected and blood samples were analyzed for antibodies against HIV, HBV and HCV, HBs antigen and viral nucleic acids for HIV and HBV. Present or past HBV infection (i.e. HBsAg and/or anti-HBc) was found in 43.4% of patients. HBsAg was detected in 4.5% (41/918) and HBV DNA in 6.1% (34/554), resulting in OHBV infection in 2.9% (16/554) of patients. OHBV infection could not be ruled out by the presence of anti-HBs (50.1%) or the absence of all HBV seromarkers (25%). A HCV-positive serostatus was associated with the IVDU transmission route, non-African ethnicity, elevated liver parameters (ASL or GGT) and low HIV viral load. Replicative HBV infection and HCV-positive serostatus both correlated with HIV resistance mutations (P = 0.001 and P = 0.028). HBV and HCV infection are frequent co-infections in HIV treatment-naive patients. These co-infections influence viral evolution, clinical parameters and serological markers. Consequently, HIV patients should routinely be tested for HBV and HCV infection before initiating HIV treatment. OHBV infection constituted almost half of all HBV infections with detectable HBV DNA. Due to a lack of risk factors indicating OHBV infection, HBV diagnosis should not only include serological markers but also the detection of HBV DNA.
Keywords HBV - HCV - Co-infection - Resistance mutations - Occult infection
S. Reuter and M. Oette contributed equally to this work.
This study is conducted for the RESINA study group.
Source
DOI: 10.1007/s00430-010-0172-zOnline First™
Original Investigation
Stefan Reuter, Mark Oette, Frank Clemens Wilhelm, Bastian Beggel, Rolf Kaiser, Melanie Balduin, Finja Schweitzer, Jens Verheyen, Ortwin Adams and Thomas Lengauer, et al.
Abstract
In HIV-infected treatment-naïve patients, we analyzed risk factors for either chronic hepatitis B (HBV) infection, occult HBV infection (OHBV) or a positive hepatitis C (HCV) serostatus. A total of 918 patients of the RESINA-cohort in Germany were included in this study. Before initiating antiretroviral therapy, clinical parameters were collected and blood samples were analyzed for antibodies against HIV, HBV and HCV, HBs antigen and viral nucleic acids for HIV and HBV. Present or past HBV infection (i.e. HBsAg and/or anti-HBc) was found in 43.4% of patients. HBsAg was detected in 4.5% (41/918) and HBV DNA in 6.1% (34/554), resulting in OHBV infection in 2.9% (16/554) of patients. OHBV infection could not be ruled out by the presence of anti-HBs (50.1%) or the absence of all HBV seromarkers (25%). A HCV-positive serostatus was associated with the IVDU transmission route, non-African ethnicity, elevated liver parameters (ASL or GGT) and low HIV viral load. Replicative HBV infection and HCV-positive serostatus both correlated with HIV resistance mutations (P = 0.001 and P = 0.028). HBV and HCV infection are frequent co-infections in HIV treatment-naive patients. These co-infections influence viral evolution, clinical parameters and serological markers. Consequently, HIV patients should routinely be tested for HBV and HCV infection before initiating HIV treatment. OHBV infection constituted almost half of all HBV infections with detectable HBV DNA. Due to a lack of risk factors indicating OHBV infection, HBV diagnosis should not only include serological markers but also the detection of HBV DNA.
Keywords HBV - HCV - Co-infection - Resistance mutations - Occult infection
S. Reuter and M. Oette contributed equally to this work.
This study is conducted for the RESINA study group.
Source
NS5B RNA Dependent RNA Polymerase Inhibitors: The Promising Approach to Treat Hepatitis C Virus Infections
Curr Med Chem. 2010 Sep 22. [Epub ahead of print]
Deore RR, Chern JW.
1343, School of Pharmacy, College of Medicine, National Taiwan University, No.1, Section 1, Jen-Ai Road, Taipei, 100, Taiwan. jwchern@ntu.edu.tw.
Abstract
Hepatitis C virus (HCV), a causative agent for non-A and non-B hepatitis, has infected approximately 3% of world's population. The current treatment option of ribavirin in combination with pegylated interferon possesses lower sustained virological response rates, and has serious disadvantages. Unfortunately, no prophylactic vaccine has been approved yet. Therefore, there is an unmet clinical need for more effective and safe anti-HCV drugs. HCV NS5B RNA dependent RNA polymerase is currently pursued as the most popular target to develop safe anti-HCV agents, as it is not expressed in uninfected cells. More than 25 pharmaceutical companies and some research groups have developed ≈50 structurally diverse scaffolds to inhibit NS5B. Here we provide comprehensive account of the drug development process of these scaffolds. NS5B polymerase inhibitors have been broadly classified in nucleoside and non nucleoside inhibitors and are sub classified according to their mechanism of action and structural diversities. With some additional considerations about the inhibitor bound NS5B enzyme X-ray crystal structure information and pharmacological aspects of the inhibitors, this review summarizes the lead identification, structure activity relationship (SAR) studies leading to the most potent NS5B inhibitors with subgenomic replicon activity.
PMID: 20858218 [PubMed - as supplied by publisher]
Source
Deore RR, Chern JW.
1343, School of Pharmacy, College of Medicine, National Taiwan University, No.1, Section 1, Jen-Ai Road, Taipei, 100, Taiwan. jwchern@ntu.edu.tw.
Abstract
Hepatitis C virus (HCV), a causative agent for non-A and non-B hepatitis, has infected approximately 3% of world's population. The current treatment option of ribavirin in combination with pegylated interferon possesses lower sustained virological response rates, and has serious disadvantages. Unfortunately, no prophylactic vaccine has been approved yet. Therefore, there is an unmet clinical need for more effective and safe anti-HCV drugs. HCV NS5B RNA dependent RNA polymerase is currently pursued as the most popular target to develop safe anti-HCV agents, as it is not expressed in uninfected cells. More than 25 pharmaceutical companies and some research groups have developed ≈50 structurally diverse scaffolds to inhibit NS5B. Here we provide comprehensive account of the drug development process of these scaffolds. NS5B polymerase inhibitors have been broadly classified in nucleoside and non nucleoside inhibitors and are sub classified according to their mechanism of action and structural diversities. With some additional considerations about the inhibitor bound NS5B enzyme X-ray crystal structure information and pharmacological aspects of the inhibitors, this review summarizes the lead identification, structure activity relationship (SAR) studies leading to the most potent NS5B inhibitors with subgenomic replicon activity.
PMID: 20858218 [PubMed - as supplied by publisher]
Source
Use of Hepatitis C–Infected Deceased Donors in Liver Transplantation
Current Hepatitis Reports
Volume 9, Number 4, 253-259, DOI: 10.1007/s11901-010-0057-z
Richard S. Mangus
Abstract
The use of hepatitis C–infected (HCV+) liver donors for HCV+ transplant recipients was previously controversial, but mounting evidence now supports this practice. HCV-related cirrhosis accounts for 45% of the liver transplants in the United States; however, these transplant recipients have worse transplant outcomes when compared to non–HCV infected (HCV-) recipients. The optimal utility of the donor graft is therefore decreased with transplantation of HCV+ recipients because the largest percentage of organs are transplanted into patients with inferior survival outcomes. Increased use of HCV+ livers, which can only be transplanted into HCV+ recipients, provides additional transplant liver allografts directly targeted to the recipient population at greatest need. As HCV+ recipients are transplanted with previously unusable organs, more HCV- donor livers are available for the HCV- recipient population, thereby increasing the utility of HCV- grafts. Therefore, increased use of HCV+ donors results in increased utility of all available liver allografts and a shorter waitlist time to transplant, because the total number of available organs is increased. This review discusses the use of HCV+ donor livers in transplantation, including donor organ evaluation, hepatitis C in liver transplantation, a review of the available literature, and the future direction of HCV+ donors in transplantation.
Keywords Liver transplant - Hepatitis C - Extended criteria donor (ECD) - Transplant outcomes
Source
Volume 9, Number 4, 253-259, DOI: 10.1007/s11901-010-0057-z
Richard S. Mangus
Abstract
The use of hepatitis C–infected (HCV+) liver donors for HCV+ transplant recipients was previously controversial, but mounting evidence now supports this practice. HCV-related cirrhosis accounts for 45% of the liver transplants in the United States; however, these transplant recipients have worse transplant outcomes when compared to non–HCV infected (HCV-) recipients. The optimal utility of the donor graft is therefore decreased with transplantation of HCV+ recipients because the largest percentage of organs are transplanted into patients with inferior survival outcomes. Increased use of HCV+ livers, which can only be transplanted into HCV+ recipients, provides additional transplant liver allografts directly targeted to the recipient population at greatest need. As HCV+ recipients are transplanted with previously unusable organs, more HCV- donor livers are available for the HCV- recipient population, thereby increasing the utility of HCV- grafts. Therefore, increased use of HCV+ donors results in increased utility of all available liver allografts and a shorter waitlist time to transplant, because the total number of available organs is increased. This review discusses the use of HCV+ donor livers in transplantation, including donor organ evaluation, hepatitis C in liver transplantation, a review of the available literature, and the future direction of HCV+ donors in transplantation.
Keywords Liver transplant - Hepatitis C - Extended criteria donor (ECD) - Transplant outcomes
Source
ZymoGenetics and Bristol-Myers Squibb to Present PEG-Interferon Lambda Phase 2a Interim Clinical Trial Results at AASLD 2010
SEATTLE & PRINCETON, N.J.--(BUSINESS WIRE)--Oct 1, 2010 - ZymoGenetics, Inc. (NASDAQ: ZGEN) and Bristol-Myers Squibb Company (NYSE: BMY) announced that interim results from Phase 2a of the EMERGE clinical trial of PEG-Interferon lambda administered with ribavirin in treatment-naïve hepatitis C virus patients, will be presented at the American Association for the Study of Liver Diseases (AASLD) annual meeting in Boston, October 29 – November 2, 2010. PEG-Interferon lambda abstracts, including clinical, pharmacokinetic and viral kinetic data along with in vitro data in combination with direct-acting antiviral agents, were published today and are available on the AASLD website at http://www.aasld.org/.
AASLD 2010 PEG-Interferon lambda Poster Presentations
Title: Pegylated Interferon Lambda (PEG-IFN-λ) Phase 2 Dose-Ranging, Active-Controlled Study in Combination with Ribavirin (RBV) for Treatment-Naïve HCV Patients (Genotypes 1, 2, 3, or 4): Safety, Viral Response, and Impact of IL-28B Host Genotype through Week 12
Abstract: 821
Presenter: A.J. Muir
Date: Sunday, October 31, 2010
Time: 8:00 AM – 5:30 PM
Title: Pharmacokinetics of PEG-Interferon lambda (PEG-IFN-λ) Following Fixed Dosing in Treatment-Naïve Hepatitis C Subjects (Single Dose Interim Data from a Dose-Ranging Phase 2A Study)
Abstract: 830
Presenter: K.A. Byrnes-Blake
Date: Sunday, October 31, 2010
Time: 8:00 AM – 5:30 PM
Title: The Effect of Treatment Group, HCV Genotype, and IL28B Genotype on Early HCV Viral Kinetics in a Phase 2A Study of PEG-Interferon lambda (PEG-IFN-λ) in Hepatitis C Patients
Abstract: 831
Presenter: J.A. Freeman
Date: Sunday, October 31, 2010
Time: 8:00 AM – 5:30 PM
Title: In vitro activity of the combination of pegylated interferon lambda (PEG-IFN-λ) with direct-acting antivirals in the HCV replicon model
Abstract: 1854
Presenter: F. McPhee
Date: Tuesday, November 2, 2010
Time: 7:00 AM - 12:00 PM
About PEG-Interferon lambda
PEG-Interferon lambda (IL-29) is a novel and first in class interferon in development for hepatitis C. The native human interferon lambda proteins are generated by the immune system in response to viral infection, and signal through a different receptor than type I interferons, such as interferon alpha. Because this receptor is present on fewer cell types within the human body, it is hypothesized that PEG-Interferon lambda may be able to demonstrate an improved safety and tolerability profile compared to alpha interferons.
About Bristol-Myers Squibb
Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information, please visit http://www.bms.com/ or follow us on Twitter at http://twitter.com/bmsnews.
About ZymoGenetics
ZymoGenetics is a biopharmaceutical company focused on the development and commercialization of therapeutic proteins for the treatment of human diseases. The company developed and is marketing RECOTHROM® Thrombin, topical (Recombinant) in the United States. ZymoGenetics has two product candidates in Phase 2 clinical development: PEG-Interferon lambda, being studied in collaboration with Bristol-Myers Squibb for treatment of hepatitis C virus infection, and IL-21, being tested as a potential treatment for metastatic melanoma. In addition, ZymoGenetics has an anti-IL-31 monoclonal antibody in preclinical development, which it expects to test initially as a treatment for atopic dermatitis. Several of the product candidates previously identified through ZymoGenetics' discovery research efforts have been licensed to and are being developed by third parties, including Merck Serono and Novo Nordisk. ZymoGenetics is eligible to receive milestone payments and royalties related to these assets. For further information, visit http://www.zymogenetics.com/.
Bristol-Myers Squibb Forward-Looking Statements
This press release contains "forward-looking statements" relating to the acquisition of ZymoGenetics by Bristol-Myers Squibb. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. No forward-looking statement can be guaranteed. Among other risks, there can be no guarantee that the acquisition will be completed, or if it is completed, that it will close within the anticipated time period. Forward-looking statements in the press release should be evaluated together with the many uncertainties that affect Bristol-Myers Squibb's business, particularly those identified in the cautionary factors discussion in Bristol-Myers Squibb's Annual Report on Form 10-K for the year ended December 31, 2009, its Quarterly Reports on Form 10-Q, and Current Reports on Form 8-K. Bristol-Myers Squibb undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise.
Except for the historical information presented herein, matters discussed herein may constitute forward-looking statements that are subject to certain risks and uncertainties that could cause actual results to differ materially from any future results, performance or achievements expressed or implied by such statements. Statements that are not historical facts, including statements preceded by, followed by, or that include the words “future”; “anticipate”; “potential”; “believe”; or similar statements are forward-looking statements. Risks and uncertainties include uncertainties as to the timing of the tender offer and merger; uncertainties as to how many of the ZymoGenetics shareholders will tender their shares in the offer; the risk that competing offers will be made; the possibility that various closing conditions for the transaction may not be satisfied or waived, including that a governmental entity may prohibit, delay or refuse to grant approval for the consummation of the transaction; the effects of disruption from the transaction making it more difficult to maintain relationships with employees, licensees, other business partners or governmental entities; as well as risks detailed from time to time in ZymoGenetics' public disclosure filings with the SEC, including its Annual Report on Form 10-K for the fiscal year ended December 31, 2009, subsequent quarterly filings on Form 10-Q and the Solicitation/Recommendation Statement filed in connection with the tender offer. The information contained in this release is as of September 28, 2010.
This press release is neither an offer to purchase nor a solicitation of an offer to sell shares of ZymoGenetics. Bristol-Myers Squibb Company and Zeus Acquisition Corporation have filed a tender offer statement with the SEC, and have mailed an offer to purchase, forms of letter or transmittal and related documents to ZymoGenetics shareholders. ZymoGenetics has filed with the SEC, and has mailed to ZymoGenetics shareholders a solicitation/recommendation statement on Schedule 14D-9. These documents contain important information about the tender offer and stockholders of ZymoGenetics are urged to read them carefully when they become available.
These documents will be available at no charge at the SEC's website at http://www.sec.gov/. The tender offer statement and the related materials may be obtained for free by directing a request by mail to Georgeson Inc., 199 Water Street, 26th Floor, New York, New York 10038 or by calling toll-free (800) 491-3096. In addition, a copy of the offer to purchase, letter or transmittal and certain other related tender offer documents (once they become available) may also be obtained free of charge from Bristol-Myers Squibb by directing a request to: Public Affairs, Telephone No.: (609) 252-6579; E-Mail: jennifer.mauer@bms.com.
ZymoGenetics Forward-Looking Statement
This press release contains forward-looking statements, including statements related to conducting and analyzing the results of clinical trials. Phrases such as “look forward” and similar expressions are intended to identify forward-looking statements. These forward-looking statements are based upon ZymoGenetics' current expectations and involve risks and uncertainties. Actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of these risks and uncertainties, which include, without limitation, risks related to ZymoGenetics' ability to design and conduct clinical trials, the possibility that clinical trial results may vary between different arms of a clinical trial and the difficulty of using prior clinical trial results to predict future outcomes, as well as those other risks detailed in ZymoGenetics' filings with the Securities and Exchange Commission, including its Annual Report on Form 10-K for the year ended December 31, 2009 and periodic reports on Form 10-Q and current reports on Form 8-K. Do not place undue reliance on these forward-looking statements, which speak only as of the date of this press release. All forward-looking statements are qualified in their entirety by this cautionary statement, and, except where required by law, ZymoGenetics undertakes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date of this press release.
PEGASYS® (Peginterferon alfa-2a) is a registered trademark of Hoffmann-La Roche
Contact: Bristol-Myers Squibb
Media
Cristi Barnett, 609-252-6028
cristi.barnett@bms.com
or
Investors
John Elicker, 609-252-4611
john.elicker@bms.com
or
ZymoGenetics
Media and Investors
Susan W. Specht, 206-442-6592
spechts@zymogenetics.com
Source
AASLD 2010 PEG-Interferon lambda Poster Presentations
Title: Pegylated Interferon Lambda (PEG-IFN-λ) Phase 2 Dose-Ranging, Active-Controlled Study in Combination with Ribavirin (RBV) for Treatment-Naïve HCV Patients (Genotypes 1, 2, 3, or 4): Safety, Viral Response, and Impact of IL-28B Host Genotype through Week 12
Abstract: 821
Presenter: A.J. Muir
Date: Sunday, October 31, 2010
Time: 8:00 AM – 5:30 PM
Title: Pharmacokinetics of PEG-Interferon lambda (PEG-IFN-λ) Following Fixed Dosing in Treatment-Naïve Hepatitis C Subjects (Single Dose Interim Data from a Dose-Ranging Phase 2A Study)
Abstract: 830
Presenter: K.A. Byrnes-Blake
Date: Sunday, October 31, 2010
Time: 8:00 AM – 5:30 PM
Title: The Effect of Treatment Group, HCV Genotype, and IL28B Genotype on Early HCV Viral Kinetics in a Phase 2A Study of PEG-Interferon lambda (PEG-IFN-λ) in Hepatitis C Patients
Abstract: 831
Presenter: J.A. Freeman
Date: Sunday, October 31, 2010
Time: 8:00 AM – 5:30 PM
Title: In vitro activity of the combination of pegylated interferon lambda (PEG-IFN-λ) with direct-acting antivirals in the HCV replicon model
Abstract: 1854
Presenter: F. McPhee
Date: Tuesday, November 2, 2010
Time: 7:00 AM - 12:00 PM
About PEG-Interferon lambda
PEG-Interferon lambda (IL-29) is a novel and first in class interferon in development for hepatitis C. The native human interferon lambda proteins are generated by the immune system in response to viral infection, and signal through a different receptor than type I interferons, such as interferon alpha. Because this receptor is present on fewer cell types within the human body, it is hypothesized that PEG-Interferon lambda may be able to demonstrate an improved safety and tolerability profile compared to alpha interferons.
About Bristol-Myers Squibb
Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information, please visit http://www.bms.com/ or follow us on Twitter at http://twitter.com/bmsnews.
About ZymoGenetics
ZymoGenetics is a biopharmaceutical company focused on the development and commercialization of therapeutic proteins for the treatment of human diseases. The company developed and is marketing RECOTHROM® Thrombin, topical (Recombinant) in the United States. ZymoGenetics has two product candidates in Phase 2 clinical development: PEG-Interferon lambda, being studied in collaboration with Bristol-Myers Squibb for treatment of hepatitis C virus infection, and IL-21, being tested as a potential treatment for metastatic melanoma. In addition, ZymoGenetics has an anti-IL-31 monoclonal antibody in preclinical development, which it expects to test initially as a treatment for atopic dermatitis. Several of the product candidates previously identified through ZymoGenetics' discovery research efforts have been licensed to and are being developed by third parties, including Merck Serono and Novo Nordisk. ZymoGenetics is eligible to receive milestone payments and royalties related to these assets. For further information, visit http://www.zymogenetics.com/.
Bristol-Myers Squibb Forward-Looking Statements
This press release contains "forward-looking statements" relating to the acquisition of ZymoGenetics by Bristol-Myers Squibb. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. No forward-looking statement can be guaranteed. Among other risks, there can be no guarantee that the acquisition will be completed, or if it is completed, that it will close within the anticipated time period. Forward-looking statements in the press release should be evaluated together with the many uncertainties that affect Bristol-Myers Squibb's business, particularly those identified in the cautionary factors discussion in Bristol-Myers Squibb's Annual Report on Form 10-K for the year ended December 31, 2009, its Quarterly Reports on Form 10-Q, and Current Reports on Form 8-K. Bristol-Myers Squibb undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise.
Except for the historical information presented herein, matters discussed herein may constitute forward-looking statements that are subject to certain risks and uncertainties that could cause actual results to differ materially from any future results, performance or achievements expressed or implied by such statements. Statements that are not historical facts, including statements preceded by, followed by, or that include the words “future”; “anticipate”; “potential”; “believe”; or similar statements are forward-looking statements. Risks and uncertainties include uncertainties as to the timing of the tender offer and merger; uncertainties as to how many of the ZymoGenetics shareholders will tender their shares in the offer; the risk that competing offers will be made; the possibility that various closing conditions for the transaction may not be satisfied or waived, including that a governmental entity may prohibit, delay or refuse to grant approval for the consummation of the transaction; the effects of disruption from the transaction making it more difficult to maintain relationships with employees, licensees, other business partners or governmental entities; as well as risks detailed from time to time in ZymoGenetics' public disclosure filings with the SEC, including its Annual Report on Form 10-K for the fiscal year ended December 31, 2009, subsequent quarterly filings on Form 10-Q and the Solicitation/Recommendation Statement filed in connection with the tender offer. The information contained in this release is as of September 28, 2010.
This press release is neither an offer to purchase nor a solicitation of an offer to sell shares of ZymoGenetics. Bristol-Myers Squibb Company and Zeus Acquisition Corporation have filed a tender offer statement with the SEC, and have mailed an offer to purchase, forms of letter or transmittal and related documents to ZymoGenetics shareholders. ZymoGenetics has filed with the SEC, and has mailed to ZymoGenetics shareholders a solicitation/recommendation statement on Schedule 14D-9. These documents contain important information about the tender offer and stockholders of ZymoGenetics are urged to read them carefully when they become available.
These documents will be available at no charge at the SEC's website at http://www.sec.gov/. The tender offer statement and the related materials may be obtained for free by directing a request by mail to Georgeson Inc., 199 Water Street, 26th Floor, New York, New York 10038 or by calling toll-free (800) 491-3096. In addition, a copy of the offer to purchase, letter or transmittal and certain other related tender offer documents (once they become available) may also be obtained free of charge from Bristol-Myers Squibb by directing a request to: Public Affairs, Telephone No.: (609) 252-6579; E-Mail: jennifer.mauer@bms.com.
ZymoGenetics Forward-Looking Statement
This press release contains forward-looking statements, including statements related to conducting and analyzing the results of clinical trials. Phrases such as “look forward” and similar expressions are intended to identify forward-looking statements. These forward-looking statements are based upon ZymoGenetics' current expectations and involve risks and uncertainties. Actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of these risks and uncertainties, which include, without limitation, risks related to ZymoGenetics' ability to design and conduct clinical trials, the possibility that clinical trial results may vary between different arms of a clinical trial and the difficulty of using prior clinical trial results to predict future outcomes, as well as those other risks detailed in ZymoGenetics' filings with the Securities and Exchange Commission, including its Annual Report on Form 10-K for the year ended December 31, 2009 and periodic reports on Form 10-Q and current reports on Form 8-K. Do not place undue reliance on these forward-looking statements, which speak only as of the date of this press release. All forward-looking statements are qualified in their entirety by this cautionary statement, and, except where required by law, ZymoGenetics undertakes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date of this press release.
PEGASYS® (Peginterferon alfa-2a) is a registered trademark of Hoffmann-La Roche
Contact: Bristol-Myers Squibb
Media
Cristi Barnett, 609-252-6028
cristi.barnett@bms.com
or
Investors
John Elicker, 609-252-4611
john.elicker@bms.com
or
ZymoGenetics
Media and Investors
Susan W. Specht, 206-442-6592
spechts@zymogenetics.com
Source
Get The Facts About Hepatitis C Viral Load
Hepatitis-Central.com
20 April 2010, 9:57 am
Those with Hepatitis C are often occupied with whether or not they have a high viral load. Despite the tendency to associate a high viral load with worsening illness, experts agree that the results of this test have little bearing on Hepatitis C disease progression.
by Nicole Cutler, L.Ac.
Upon being diagnosed with Hepatitis C, the myriad of subsequent tests can seem like a flurry of being poked and prodded. As one of the primary markers physicians use to assess this illness, viral load’s significance can be misleading. One of the most common misconceptions among Hepatitis C patients is that a higher viral load indicates a greater severity of their disease. This causes many people to incorrectly conclude that if their viral load is high they are in much more serious trouble than if it was low. However, the primary purpose of viral load testing is to determine someone’s candidacy, progress and success for Hepatitis C antiviral treatment.
Hepatitis C is a viral infection of the liver. However, the virus does make its way outside of the liver. This is why Hepatitis C can be measured in the bloodstream. A viral load test determines how many viral particles are floating around in the blood. These particles contain RNA, copies of Hepatitis C’s genetic material. There are three types of tests used to evaluate viral load:
1. PCR (Polymerase Chain Reaction) - PCR tests measure Hepatitis C RNA in the blood to tell if there is an active infection. This test can measure small amounts of the virus (5-10 IU/mL).
2. bDNA (Branched-chain DNA) - The bDNA test only measures medium to high viral loads above 50 IU/mL. This means that if a person has a viral load below 50 IU/mL, a bDNA test may not be able to detect the virus.
3. TMA (Transcription-mediated amplification) – The TMA test also measures Hepatitis C RNA in a blood sample. The TMA test can measure very small amounts of the virus (as few as 5-10 IU/mL).
Results of these viral load tests can be translated in two ways – either in the number of copies of the virus per milliliter or by International Units per milliliter (IU/mL). Physicians often differ in their opinion about what constitutes a high or a low viral load measurement. While these ranges may not be completely agreed on, the following measurements generally denote a high or low Hepatitis C viral load:
When expressed in terms of copies per mL:
· Low = fewer than 2 million copies
· High = greater than 2 million copies
When expressed in terms of International Units per mL:
· Low = fewer than 800,000 IU/mL
· High = greater than 800,000 IU/mL
Viral load does not appear to correlate with a person’s wellness. In fact, a person with a viral load below 200,000 (in terms of copies/mL) may not be able to get out of bed because of their Hepatitis C infection – while someone with a viral load of 10 million (in terms of copies/mL) could feel fine. When it comes to determining liver disease severity, a liver biopsy – or similarly equivalent method – is the only way for a physician to accurately determine his or her patient’s health. This is because a liver biopsy – not viral load – physically examines liver tissue to see how much damage actually exists.
Although Hepatitis C viral load is not a measure of liver disease severity, it is an important marker for several other reasons:
1. A viral load test can determine if the Hepatitis C virus is still present in the body, or if it has been cleared.
2. The chance of a pregnant woman passing the virus on to her child is very low – unless she has a high viral load. An expectant mother with a high viral load has a slightly greater chance of passing the virus to her baby.
3. Numerous studies have shown that people with lower Hepatitis C viral loads respond better to interferon therapy than those with higher viral loads. This information may help physicians determine who is a good candidate for interferon therapy.
4. For those on interferon treatment, viral load testing helps physicians determine if the treatment is working and how long a person should take it.
When a physician evaluates your viral load to see if you are responding to interferon treatment, they look at this number in terms of logarithims:
· A 1-log change is a 10-fold difference.
· Significant changes in viral load are a 2-log difference or a 100-fold change. Differentiating between a 1- and 2-log change can be deceiving.
· A viral load of 800,000 that drops down to 400,000 might appear to be a big drop but it’s only changed by a factor of two – which is just a fraction of a 1-log change.
· However, a change from 800,000 to 8,000 would be significant – as that is a 100-fold change.
· In general, if a person’s viral load has dropped 2 logs or more after 12 weeks of antiviral treatment, there is a greater chance that his or her treatment will be successful.
Besides viral load’s use for monitoring during treatment, it is also used to evaluate the success of Hepatitis C treatment. Viral load is measured to see if the person achieved a sustained virilogic response (SVR). Achieving SVR means that six months after antiviral treatment was completed, viral load tests found no detectable Hepatitis C virus in the blood.
Hepatitis C viral load will normally fluctuate throughout the course of anyone’s illness. In and of itself, viral load is not a reason for concern. It may sound like a good measure of how someone is faring with Hepatitis C. But outside of this test’s use to determine if someone is a candidate for treatment, to monitor treatment or to see if treatment was successful, Hepatitis C viral load reveals very little about the degree of a person’s liver disease.
References:
http://www.ehow.com/how_4448469_understand-hepatitis-c-viral-load.html, How to Understand Hepatitis C Viral Load, Richard Ferri, Retrieved December 3, 2009, eHow, Inc., 2009.
http://www.hcvadvocate.org/hepatitis/Basics/Viralload_09.pdf, HCV Viral Load Tests, Alan Franciscus, Retrieved December 3, 2009, The Hepatitis C Support Project, 2009.
Source
20 April 2010, 9:57 am
Those with Hepatitis C are often occupied with whether or not they have a high viral load. Despite the tendency to associate a high viral load with worsening illness, experts agree that the results of this test have little bearing on Hepatitis C disease progression.
by Nicole Cutler, L.Ac.
Upon being diagnosed with Hepatitis C, the myriad of subsequent tests can seem like a flurry of being poked and prodded. As one of the primary markers physicians use to assess this illness, viral load’s significance can be misleading. One of the most common misconceptions among Hepatitis C patients is that a higher viral load indicates a greater severity of their disease. This causes many people to incorrectly conclude that if their viral load is high they are in much more serious trouble than if it was low. However, the primary purpose of viral load testing is to determine someone’s candidacy, progress and success for Hepatitis C antiviral treatment.
Hepatitis C is a viral infection of the liver. However, the virus does make its way outside of the liver. This is why Hepatitis C can be measured in the bloodstream. A viral load test determines how many viral particles are floating around in the blood. These particles contain RNA, copies of Hepatitis C’s genetic material. There are three types of tests used to evaluate viral load:
1. PCR (Polymerase Chain Reaction) - PCR tests measure Hepatitis C RNA in the blood to tell if there is an active infection. This test can measure small amounts of the virus (5-10 IU/mL).
2. bDNA (Branched-chain DNA) - The bDNA test only measures medium to high viral loads above 50 IU/mL. This means that if a person has a viral load below 50 IU/mL, a bDNA test may not be able to detect the virus.
3. TMA (Transcription-mediated amplification) – The TMA test also measures Hepatitis C RNA in a blood sample. The TMA test can measure very small amounts of the virus (as few as 5-10 IU/mL).
Results of these viral load tests can be translated in two ways – either in the number of copies of the virus per milliliter or by International Units per milliliter (IU/mL). Physicians often differ in their opinion about what constitutes a high or a low viral load measurement. While these ranges may not be completely agreed on, the following measurements generally denote a high or low Hepatitis C viral load:
When expressed in terms of copies per mL:
· Low = fewer than 2 million copies
· High = greater than 2 million copies
When expressed in terms of International Units per mL:
· Low = fewer than 800,000 IU/mL
· High = greater than 800,000 IU/mL
Viral load does not appear to correlate with a person’s wellness. In fact, a person with a viral load below 200,000 (in terms of copies/mL) may not be able to get out of bed because of their Hepatitis C infection – while someone with a viral load of 10 million (in terms of copies/mL) could feel fine. When it comes to determining liver disease severity, a liver biopsy – or similarly equivalent method – is the only way for a physician to accurately determine his or her patient’s health. This is because a liver biopsy – not viral load – physically examines liver tissue to see how much damage actually exists.
Although Hepatitis C viral load is not a measure of liver disease severity, it is an important marker for several other reasons:
1. A viral load test can determine if the Hepatitis C virus is still present in the body, or if it has been cleared.
2. The chance of a pregnant woman passing the virus on to her child is very low – unless she has a high viral load. An expectant mother with a high viral load has a slightly greater chance of passing the virus to her baby.
3. Numerous studies have shown that people with lower Hepatitis C viral loads respond better to interferon therapy than those with higher viral loads. This information may help physicians determine who is a good candidate for interferon therapy.
4. For those on interferon treatment, viral load testing helps physicians determine if the treatment is working and how long a person should take it.
When a physician evaluates your viral load to see if you are responding to interferon treatment, they look at this number in terms of logarithims:
· A 1-log change is a 10-fold difference.
· Significant changes in viral load are a 2-log difference or a 100-fold change. Differentiating between a 1- and 2-log change can be deceiving.
· A viral load of 800,000 that drops down to 400,000 might appear to be a big drop but it’s only changed by a factor of two – which is just a fraction of a 1-log change.
· However, a change from 800,000 to 8,000 would be significant – as that is a 100-fold change.
· In general, if a person’s viral load has dropped 2 logs or more after 12 weeks of antiviral treatment, there is a greater chance that his or her treatment will be successful.
Besides viral load’s use for monitoring during treatment, it is also used to evaluate the success of Hepatitis C treatment. Viral load is measured to see if the person achieved a sustained virilogic response (SVR). Achieving SVR means that six months after antiviral treatment was completed, viral load tests found no detectable Hepatitis C virus in the blood.
Hepatitis C viral load will normally fluctuate throughout the course of anyone’s illness. In and of itself, viral load is not a reason for concern. It may sound like a good measure of how someone is faring with Hepatitis C. But outside of this test’s use to determine if someone is a candidate for treatment, to monitor treatment or to see if treatment was successful, Hepatitis C viral load reveals very little about the degree of a person’s liver disease.
References:
http://www.ehow.com/how_4448469_understand-hepatitis-c-viral-load.html, How to Understand Hepatitis C Viral Load, Richard Ferri, Retrieved December 3, 2009, eHow, Inc., 2009.
http://www.hcvadvocate.org/hepatitis/Basics/Viralload_09.pdf, HCV Viral Load Tests, Alan Franciscus, Retrieved December 3, 2009, The Hepatitis C Support Project, 2009.
Source
The Importance of Laboratory Test Results in Hepatitis C Infection
David Bernstein, MD, FACP, FACG
Director of Hepatology
North Shore University Hospital
Associate Professor of Medicine
SUNY-Downstate School of Medicine
Most people with hepatitis C feel well and have no specific findings on physical examination that would lead a health care provider to suspect liver disease. Even the vast majority of people with liver disease that has advanced to cirrhosis have a normal physical examination. Therefore, the evaluation and treatment of liver disease, in particular hepatitis C, places a large emphasis on laboratory tests results to diagnose, stage and predict and evaluate response to therapy.
The liver has several general functions and it is often called both the body’s manufacturing center and its filtering plant. Blood tests used to evaluate the liver can be divided into those representing liver cell damage, cholestasis or liver function. The serum aminotransaminases, alanine aminotransferase (ALT or SGPT) and aspartate aminotransferase (AST or SGOT) are part of most automated blood chemistry panels. Elevation of these enzymes is caused by damage to the hepatocyte or liver cell. The degree of elevation may be important in acute disease but is unimportant in chronic disease. The most common causes of elevated aminotransaminases are fatty liver, viral hepatitis, medication induced hepatitis, autoimmune hepatitis and alcoholic liver disease. The tests are a reflection of cell damage and death but are not liver function tests. Although many patients and physicians refer to these tests as “liver function tests”, this term is incorrect and they do not reflect the liver’s ability to either synthesize or metabolize various chemicals. Therefore, an abnormality in these tests does not mean that the liver is not functioning. In fact, the vast majority of patients with elevated aminotransaminases, regardless of degree, have normal liver function.
Cholestatic liver disease is any condition leading to the obstruction of bile ducts in either the liver or biliary tree. Elevation of the enzymes alkaline phosphatase and gamma-glutamyl transpeptidase are indicative of this type of disease. Conditions that commonly lead to the elevation of these enzymes include primary biliary cirrhosis, primary sclerosing cholangitis and gallstone disease.
Bilirubin is the final breakdown product of heme, the majority of which comes from hemoglobin. Bilirubin can be elevated in many liver-related and non-liver- related conditions and it may be elevated in conditions which lead to liver cell damage and cholestasis. The level of serum bilirubin is not a sensitive indicator of liver function and it may not accurately reflect the degree of liver damage.
Albumin and blood clotting factors are proteins made in the liver. Blood tests such as the serum albumin and prothrombin time are measures of these proteins. As these tests evaluate the functional integrity of the liver, they can be correctly called “liver function tests”. Abnormalities of these tests are of concern and are indicative of extensive liver damage.
The most common laboratory abnormality seen in chronic hepatitis C infection is an isolated, elevated alanine aminotransferase (ALT) although as many as 60% of hepatitis C infected patients will have a normal ALT level. The level of serum ALT elevation does not correlate with histological disease and may be normal in any stage of chronic hepatitis C. Therefore, patients with minimal ALT elevations should be evaluated for the presence of chronic hepatitis. In advanced disease, an increase in alkaline phosphatase and total bilirubin as well as thrombocytopenia (low platelets) may be seen.
In the patient with risk factors for hepatitis C or an abnormal ALT, the most practical method of diagnosing HCV infection is by obtaining a second generation enzyme linked immunosorbent assay (EIA) antibody to hepatitis C (anti-HCV). False-positive results may occur at a rate of 10-20% and are usually seen in the presence of autoimmune disease, hypergammaglobulinemia and low-risk blood donors. False negative results may occur in immunosuppressed patients, including people infected with the human immunodeficiency virus. In early infection, anti-HCV testing may be negative, as antibodies may not develop until 4-6 weeks after exposure. Unfortunately, a positive hepatitis C antibody does not distinguish acute from chronic disease or active from past infection nor is it a sign of immunity or protection. Therefore, a positive EIA anti-HCV test is a marker that hepatitis C may be present and it must be followed by confirmatory viral load testing.
The recombinant immunoblot assay (RIBA) is another type of antibody test with limited utility. As with EIA antibody tests, it does not distinguish between acute or chronic disease or between past and active infection. Therefore, it adds little to the care of a patient with a positive hepatitis C antibody by the EIA method and known risk factors except extra expense. The NIH consensus conference on hepatitis C has recommended that it be used as a confirmatory test in patients without known risk factors who test positive for the EIA anti-HCV to eliminate the possibility of a false positive EIA. RIBA testing is not influenced by the presence of autoimmune disease or hypergammaglobulinemia. In clinical practice, this test has little if any utility and, except for rare exceptions, it should not be obtained.
Confirmatory tests for the presence of hepatitis C infection are those tests that determine the presence of hepatitis C viral particles (HCV-RNA) in the blood. A positive HCV-RNA in the serum confirms the diagnosis of active hepatitis C. This type of viral testing may be either qualitative or quantitative. Qualitative testing is more sensitive and specific than quantitative testing and results are reported as either positive or negative. Quantitative testing reports on the actual measured amount of viral particles in the serum and the viral levels are usually expressed as thousands or millions of international units. Of note, quantitative viral testing may be falsely negative if viral levels are below the lower limit of detection of the assay being used. Therefore, qualitative HCV-RNA testing is used for diagnosis while quantitative testing should be reserved for use during treatment. It is important to note that the level of virus does not correlate with prognosis, underlying liver histology or how ill a person feels. Therefore, a patient with a viral level of 3,000,000 international units does not have a worse prognosis nor is the person any sicker than someone with a viral count of 200,000 international units. Small fluctuations in HCV-RNA level are equally unimportant. A patient whose viral level has decreased from five to one million international units has shown no significant change in viral level and should not be rejoicing. The converse is also true and an elevation from one to five million international units should not lead a patient to be upset. It is important to understand the relative lack of importance of viral level in the untreated hepatitis C patient. Misconceptions about viral levels often lead to tremendous angst among patients who insist on comparing numbers in the waiting room, are upset by the initial level of viremia or feel falsely relieved or upset with small changes in HCV-RNA viral load. Recently, however, it has been suggested that in the population co-infected with hepatitis C and HIV, a higher hepatitis C viral load is associated with a more rapid progression to advanced disease. As regards viral level and its significance, the co-infected patient appears to behave differently than the HCV mono-infected person. Quantitative viral load testing should not be repeated yearly or more often as it adds little to the care of the untreated patient other than increased expense and anxiety. These tests, however, should be followed serially in someone undergoing anti-viral therapy, as the goal of therapy is the loss of detectable serum HCV-RNA.
Several other liver tests are frequently obtained in patients with hepatitis C. The serum alpha-fetoprotein is a marker of liver cancer but it may be mildly elevated in patients with chronic hepatitis C in the absence of liver cancer. If it is elevated, this test should be followed closely. Autoimmune markers may be present in as many as 25% patients with hepatitis C without the presence of autoimmune disease. These markers include an anti-nuclear antibody, smooth muscle antibody, anti-mitochondrial antibody or anti-thyroid antibodies. The presence of these antibodies does not appear to influence disease progression. Patients in whom autoimmune disease is suspected should be adequately evaluated before the presence of autoantibodies is attributed to HCV infection.
The adequate interpretation of laboratory test results is very important to understand the evaluation of hepatitis C infection. Unfortunately, in the majority of cases, these blood tests are unable to accurately predict current disease stage or possible disease progression. Therefore, despite all these advanced tests, the performance of a liver biopsy cannot be emphasized enough as this is the best test to accurately stage the disease and predict disease progression.
Source
Director of Hepatology
North Shore University Hospital
Associate Professor of Medicine
SUNY-Downstate School of Medicine
Most people with hepatitis C feel well and have no specific findings on physical examination that would lead a health care provider to suspect liver disease. Even the vast majority of people with liver disease that has advanced to cirrhosis have a normal physical examination. Therefore, the evaluation and treatment of liver disease, in particular hepatitis C, places a large emphasis on laboratory tests results to diagnose, stage and predict and evaluate response to therapy.
The liver has several general functions and it is often called both the body’s manufacturing center and its filtering plant. Blood tests used to evaluate the liver can be divided into those representing liver cell damage, cholestasis or liver function. The serum aminotransaminases, alanine aminotransferase (ALT or SGPT) and aspartate aminotransferase (AST or SGOT) are part of most automated blood chemistry panels. Elevation of these enzymes is caused by damage to the hepatocyte or liver cell. The degree of elevation may be important in acute disease but is unimportant in chronic disease. The most common causes of elevated aminotransaminases are fatty liver, viral hepatitis, medication induced hepatitis, autoimmune hepatitis and alcoholic liver disease. The tests are a reflection of cell damage and death but are not liver function tests. Although many patients and physicians refer to these tests as “liver function tests”, this term is incorrect and they do not reflect the liver’s ability to either synthesize or metabolize various chemicals. Therefore, an abnormality in these tests does not mean that the liver is not functioning. In fact, the vast majority of patients with elevated aminotransaminases, regardless of degree, have normal liver function.
Cholestatic liver disease is any condition leading to the obstruction of bile ducts in either the liver or biliary tree. Elevation of the enzymes alkaline phosphatase and gamma-glutamyl transpeptidase are indicative of this type of disease. Conditions that commonly lead to the elevation of these enzymes include primary biliary cirrhosis, primary sclerosing cholangitis and gallstone disease.
Bilirubin is the final breakdown product of heme, the majority of which comes from hemoglobin. Bilirubin can be elevated in many liver-related and non-liver- related conditions and it may be elevated in conditions which lead to liver cell damage and cholestasis. The level of serum bilirubin is not a sensitive indicator of liver function and it may not accurately reflect the degree of liver damage.
Albumin and blood clotting factors are proteins made in the liver. Blood tests such as the serum albumin and prothrombin time are measures of these proteins. As these tests evaluate the functional integrity of the liver, they can be correctly called “liver function tests”. Abnormalities of these tests are of concern and are indicative of extensive liver damage.
The most common laboratory abnormality seen in chronic hepatitis C infection is an isolated, elevated alanine aminotransferase (ALT) although as many as 60% of hepatitis C infected patients will have a normal ALT level. The level of serum ALT elevation does not correlate with histological disease and may be normal in any stage of chronic hepatitis C. Therefore, patients with minimal ALT elevations should be evaluated for the presence of chronic hepatitis. In advanced disease, an increase in alkaline phosphatase and total bilirubin as well as thrombocytopenia (low platelets) may be seen.
In the patient with risk factors for hepatitis C or an abnormal ALT, the most practical method of diagnosing HCV infection is by obtaining a second generation enzyme linked immunosorbent assay (EIA) antibody to hepatitis C (anti-HCV). False-positive results may occur at a rate of 10-20% and are usually seen in the presence of autoimmune disease, hypergammaglobulinemia and low-risk blood donors. False negative results may occur in immunosuppressed patients, including people infected with the human immunodeficiency virus. In early infection, anti-HCV testing may be negative, as antibodies may not develop until 4-6 weeks after exposure. Unfortunately, a positive hepatitis C antibody does not distinguish acute from chronic disease or active from past infection nor is it a sign of immunity or protection. Therefore, a positive EIA anti-HCV test is a marker that hepatitis C may be present and it must be followed by confirmatory viral load testing.
The recombinant immunoblot assay (RIBA) is another type of antibody test with limited utility. As with EIA antibody tests, it does not distinguish between acute or chronic disease or between past and active infection. Therefore, it adds little to the care of a patient with a positive hepatitis C antibody by the EIA method and known risk factors except extra expense. The NIH consensus conference on hepatitis C has recommended that it be used as a confirmatory test in patients without known risk factors who test positive for the EIA anti-HCV to eliminate the possibility of a false positive EIA. RIBA testing is not influenced by the presence of autoimmune disease or hypergammaglobulinemia. In clinical practice, this test has little if any utility and, except for rare exceptions, it should not be obtained.
Confirmatory tests for the presence of hepatitis C infection are those tests that determine the presence of hepatitis C viral particles (HCV-RNA) in the blood. A positive HCV-RNA in the serum confirms the diagnosis of active hepatitis C. This type of viral testing may be either qualitative or quantitative. Qualitative testing is more sensitive and specific than quantitative testing and results are reported as either positive or negative. Quantitative testing reports on the actual measured amount of viral particles in the serum and the viral levels are usually expressed as thousands or millions of international units. Of note, quantitative viral testing may be falsely negative if viral levels are below the lower limit of detection of the assay being used. Therefore, qualitative HCV-RNA testing is used for diagnosis while quantitative testing should be reserved for use during treatment. It is important to note that the level of virus does not correlate with prognosis, underlying liver histology or how ill a person feels. Therefore, a patient with a viral level of 3,000,000 international units does not have a worse prognosis nor is the person any sicker than someone with a viral count of 200,000 international units. Small fluctuations in HCV-RNA level are equally unimportant. A patient whose viral level has decreased from five to one million international units has shown no significant change in viral level and should not be rejoicing. The converse is also true and an elevation from one to five million international units should not lead a patient to be upset. It is important to understand the relative lack of importance of viral level in the untreated hepatitis C patient. Misconceptions about viral levels often lead to tremendous angst among patients who insist on comparing numbers in the waiting room, are upset by the initial level of viremia or feel falsely relieved or upset with small changes in HCV-RNA viral load. Recently, however, it has been suggested that in the population co-infected with hepatitis C and HIV, a higher hepatitis C viral load is associated with a more rapid progression to advanced disease. As regards viral level and its significance, the co-infected patient appears to behave differently than the HCV mono-infected person. Quantitative viral load testing should not be repeated yearly or more often as it adds little to the care of the untreated patient other than increased expense and anxiety. These tests, however, should be followed serially in someone undergoing anti-viral therapy, as the goal of therapy is the loss of detectable serum HCV-RNA.
Several other liver tests are frequently obtained in patients with hepatitis C. The serum alpha-fetoprotein is a marker of liver cancer but it may be mildly elevated in patients with chronic hepatitis C in the absence of liver cancer. If it is elevated, this test should be followed closely. Autoimmune markers may be present in as many as 25% patients with hepatitis C without the presence of autoimmune disease. These markers include an anti-nuclear antibody, smooth muscle antibody, anti-mitochondrial antibody or anti-thyroid antibodies. The presence of these antibodies does not appear to influence disease progression. Patients in whom autoimmune disease is suspected should be adequately evaluated before the presence of autoantibodies is attributed to HCV infection.
The adequate interpretation of laboratory test results is very important to understand the evaluation of hepatitis C infection. Unfortunately, in the majority of cases, these blood tests are unable to accurately predict current disease stage or possible disease progression. Therefore, despite all these advanced tests, the performance of a liver biopsy cannot be emphasized enough as this is the best test to accurately stage the disease and predict disease progression.
Source
Understanding the functions of your liver
THE liver is the largest internal organ of the body. this vital organ is crucial to the smooth functioning of the human body.
It metabolises most of the nutrients that are absorbed by the intestine and detoxifies the blood by removing medications, alcohol and potentially harmful chemicals from the bloodstream – processing them chemically so that they can be expelled from the body by the digestive or urinary systems.
The liver also produces clotting factors and other proteins, stores certain vitamins, minerals (including iron) and sugars, regulates fat stores, and controls the production and excretion of cholesterol.
It is an amazing organ that can regenerate its cells within a few weeks. in fact, the liver can tolerate a fair amount of “abuse” and will only show signs of injury when the hurt is very advanced.
Liver disorders include hepatitis and cirrhosis. Hepatitis is inflammation of the liver and cirrhosis is scarring of the liver. these two conditions may progress to liver cancer if they are not monitored or treated properly.
Cirrhosis of the liver happens when your liver has a complication of many diseases. Anatomically, your liver will have a lot of scar tissue manifested in nodules and fibrous tissue that is hard.
When this happens, it could be due to the following factors:
1. That your liver is damaged by chronic liver disease.
2. That there is a lot of damaged liver tissue, leading to inflammation and subsequent repair and replacement by fibrous or scar tissue.
3. That there is regeneration of liver tissue from the cells that are still remaining, but it doesn’t go quite normally, leading to regenerative nodules.
If it were only the structure of the liver that is affected, cirrhosis would just be an ugly feature on an ultrasound. unfortunately, this is not a common occurance. usually, your liver functions are also affected and that’s when the problem starts.
As the largest internal organ of the body, the liver performs the following essential functions:
1. it controls the levels of fats, amino acids and glucose in your blood. Stores glycogen (glucose in another form), iron, vitamins and other essential nutrients.
2. it manufactures bile and aids in your digestive process, especially in the breakdown of fats.
3. it detoxifies your blood by clearing it of toxic wastes, breaking them down and getting rid of them either through your faeces or releasing them into your blood in smaller particles to be further cleared by your kidneys.
4. Manufactures and regulates various hormones, enzymes and clotting factors.
5. Fights infections, especially through macrophages.
Cirrhosis of the liver occurs because the liver anatomy is so scarred that it interferes with the liver cells’ functions, and thus renders the liver to be unable to perform many of its functions well.
The trouble with cirrhosis is that it has no clear symptoms or very few which are nondescript, like tiredness or fatigue. So you will not know that you have it till liver failure creeps up on you by which time may be a small too late.
Some symptoms associated with cirrhosis are fatigue, weakness, loss of appetite, itching, and sometimes jaundice if there is accumulation of bilirubin in your blood. Your clotting factors may also be affected and you can have simple bruising of your skin.
Often when cirrhosis becomes severe, you will develop complications. these complications can be a lot more clear in their symptoms and usually are the first physical sign that something is wrong.
1) You begin to retain water, leading to a condition called ascites, where there is excessive water in your peritoneal cavity (cavity within your abdomen). there is also a lot of water accumulated in your ankles and feet, manifested by swelling. the ascites is a magnet for bacteria to grow, and you may have an infection.
2) You can also have bleeding from oesophageal veins. in cirrhosis, the scar tissue blocks the flow of blood from the intestines to the heart, resulting in the distension of the portal vein. (This is the vein that is very important in the digestive process.) the back pressure leads to distension of your veins in the lower part of your oesophagus. these veins can bleed, leading to you vomiting blood (haematemesis). this can be life-threatening.
3) this pressure can also cause your spleen to distend and become so swollen that it sometimes becomes a hard mass in your abdomen. this gigantic spleen traps your blood cells and causes you to have anaemia and prolonged bleeding.
4) Because your liver cannot detoxify your body, this can lead to toxic substances in your blood. this goes to your brain and causes sleepiness during the day, irritability, confusion, loss of concentration, and finally coma and death.
5) Cirrhosis greatly increases the risk of you getting liver cancer
Causes of liver cirrhosis include excessive alcohol consumption that leads to hurt of your liver cells, resulting in a fatty liver (something which is heightened by obesity); chronic viral hepatitis (B,C); genetic liver disorders; and possibly anything that can hurt your liver can lead to cirrhosis.
Avoid excessive alcohol consumption, and make sure you have your hepatitis jabs, especially if you intend to travel to anyplace where hepatitis is viral . Lose any excess weight, and ensure you go for frequent check-ups
As the saying goes, prevention is better than cure and here are some measures you can take to preserve your liver health:
Poor nutrition rarely causes liver disease but excellent nutrition in the form of a balanced diet will enable the liver to perform its many various functions efficiently, resulting in better overall health. it can also help liver cells damaged by hepatitis viruses to regenerate, forming new liver cells.
But, whilst it is important to take vitamins and minerals, please note that an excess of Vitamin A is toxic to the liver and should be taken in moderation.
2. Limit intake of calories.
Excess calories in the form of carbohydrates can add to liver dysfunction and can cause fat deposits in the liver, contributing to fatty liver.
No more than 30% of a person’s total calories should come from fat because of the danger to the cardiovascular system. in order to estimate your daily calorie needs, you will need a minimum of 15 calories a day for each pound you weigh
3. Hold the alcohol
Liquor, beer and wine are hard for the liver to metabolise. the daily recommended alcohol intake is three units/drinks for men and two units/drinks for women.
As a general guide, one unit of alcohol translates to half a pint of ordinary strength beer, a small measure (25ml) of spirits or a standard measure (50ml) of fortified wine such as sherry or port.
Having three drinks or more per day should be avoided, as it may lead to alcoholic hepatitis and cirrhosis. People with liver disease should never drink alcohol at all. the same goes for individuals who are taking medication ? mixing alcohol with painkillers or other types of medications can be perilous to your liver.
In particular, the mixture of alcohol and acetaminophen (an ingredient in pain killers and cough medication) can cause sudden, severe hepatitis and even fatal liver failure. If you are not sure which medications to take in combination, please consult your doctor.
4. Beware “nutritional therapies”
Herbal treatments and alternative liver medicines should undergo rigorous scientific study before they can be recommended.
“Natural” or diet treatments and herbal remedies can be quite perilous. Plants of the Crotalaria, Senecio and Heliotopium families, as well as chaparral, mistletoe, skullcap, germander, comfrey, margosa oil, mate tea, Gordolobo yerba tea, pennyroyal, and Jin Blu Huan are all toxic to the liver.
Several scientific studies suggest that substances in milk thistle may protect the liver from harmful substances such as acetaminophen, which can cause liver hurt. it is also believed that milk thistle has antioxidant and anti-inflammatory properties, and it may help the liver repair itself by growing new cells.
5. stop smoking and stay away from toxic fumes and liquids.
Fumes from paint thinners, bug sprays, and other aerosol sprays are picked up by the tiny blood vessels in your lungs and carried to your liver where they are detoxified and discharged in your bile.
The amount and concentration of those chemicals should be controlled to prevent liver hurt. make certain you have excellent ventilation, use a mask, cover your skin, and wash off any chemicals you get on your skin with soap and water as soon as possible.
Hands should be washed with soap and water following bowel movements and before food preparation and consumption. this will help prevent the spread of hepatitis A.
Avoid sex with multiple partners or wear protection where unavoidable. Hepatitis B and C are transmitted through blood and body fluids. So use condoms and avoid sharing your personal items such as toothbrush, razor or manicure sets, especially if your partner may be suffering from a liver disease.
Vaccination for hepatitis A and B is available. an immunisation programme for hepatitis B has been in place for all children and adults since 1989 to prevent hepatitis B infection. it is essential to vaccinate newborns for hepatitis B as infections in this group will result in 90% chronic infection. there is no vaccination available for hepatitis C.
Chronic liver infection can lead to cirrhosis, where there are areas of scarring and liver cell regeneration within the liver.
Cirrhosis can lead to liver cancer, which is often diagnosed too late as few symptoms appear until it has reached an advanced stage. Signs and symptoms of liver cancer include right upper abdominal pain, jaundice (yellowing of the skin), abdominal swelling, weight loss, fatigue, simple bruising or bleeding.
Apart from surgery, for which most liver cancer patients are ineligible due to the advanced stages of the disease at time of diagnosis, there is currently an oral treatment that has been found to be effective in targeting the liver cancer cells specifically and can be used in patients who are unsuitable for surgery.
Sorafenib is an oral treatment available for the treatment of advanced liver cancer.
Keeping the liver healthy is essential to keeping your entire being healthy, so take excellent care of your liver, so that it can take care of you.
Source
It metabolises most of the nutrients that are absorbed by the intestine and detoxifies the blood by removing medications, alcohol and potentially harmful chemicals from the bloodstream – processing them chemically so that they can be expelled from the body by the digestive or urinary systems.
The liver also produces clotting factors and other proteins, stores certain vitamins, minerals (including iron) and sugars, regulates fat stores, and controls the production and excretion of cholesterol.
It is an amazing organ that can regenerate its cells within a few weeks. in fact, the liver can tolerate a fair amount of “abuse” and will only show signs of injury when the hurt is very advanced.
Liver disorders include hepatitis and cirrhosis. Hepatitis is inflammation of the liver and cirrhosis is scarring of the liver. these two conditions may progress to liver cancer if they are not monitored or treated properly.
Cirrhosis of the liver happens when your liver has a complication of many diseases. Anatomically, your liver will have a lot of scar tissue manifested in nodules and fibrous tissue that is hard.
When this happens, it could be due to the following factors:
1. That your liver is damaged by chronic liver disease.
2. That there is a lot of damaged liver tissue, leading to inflammation and subsequent repair and replacement by fibrous or scar tissue.
3. That there is regeneration of liver tissue from the cells that are still remaining, but it doesn’t go quite normally, leading to regenerative nodules.
If it were only the structure of the liver that is affected, cirrhosis would just be an ugly feature on an ultrasound. unfortunately, this is not a common occurance. usually, your liver functions are also affected and that’s when the problem starts.
As the largest internal organ of the body, the liver performs the following essential functions:
1. it controls the levels of fats, amino acids and glucose in your blood. Stores glycogen (glucose in another form), iron, vitamins and other essential nutrients.
2. it manufactures bile and aids in your digestive process, especially in the breakdown of fats.
3. it detoxifies your blood by clearing it of toxic wastes, breaking them down and getting rid of them either through your faeces or releasing them into your blood in smaller particles to be further cleared by your kidneys.
4. Manufactures and regulates various hormones, enzymes and clotting factors.
5. Fights infections, especially through macrophages.
Cirrhosis of the liver occurs because the liver anatomy is so scarred that it interferes with the liver cells’ functions, and thus renders the liver to be unable to perform many of its functions well.
The trouble with cirrhosis is that it has no clear symptoms or very few which are nondescript, like tiredness or fatigue. So you will not know that you have it till liver failure creeps up on you by which time may be a small too late.
Some symptoms associated with cirrhosis are fatigue, weakness, loss of appetite, itching, and sometimes jaundice if there is accumulation of bilirubin in your blood. Your clotting factors may also be affected and you can have simple bruising of your skin.
Often when cirrhosis becomes severe, you will develop complications. these complications can be a lot more clear in their symptoms and usually are the first physical sign that something is wrong.
1) You begin to retain water, leading to a condition called ascites, where there is excessive water in your peritoneal cavity (cavity within your abdomen). there is also a lot of water accumulated in your ankles and feet, manifested by swelling. the ascites is a magnet for bacteria to grow, and you may have an infection.
2) You can also have bleeding from oesophageal veins. in cirrhosis, the scar tissue blocks the flow of blood from the intestines to the heart, resulting in the distension of the portal vein. (This is the vein that is very important in the digestive process.) the back pressure leads to distension of your veins in the lower part of your oesophagus. these veins can bleed, leading to you vomiting blood (haematemesis). this can be life-threatening.
3) this pressure can also cause your spleen to distend and become so swollen that it sometimes becomes a hard mass in your abdomen. this gigantic spleen traps your blood cells and causes you to have anaemia and prolonged bleeding.
4) Because your liver cannot detoxify your body, this can lead to toxic substances in your blood. this goes to your brain and causes sleepiness during the day, irritability, confusion, loss of concentration, and finally coma and death.
5) Cirrhosis greatly increases the risk of you getting liver cancer
Causes of liver cirrhosis include excessive alcohol consumption that leads to hurt of your liver cells, resulting in a fatty liver (something which is heightened by obesity); chronic viral hepatitis (B,C); genetic liver disorders; and possibly anything that can hurt your liver can lead to cirrhosis.
Avoid excessive alcohol consumption, and make sure you have your hepatitis jabs, especially if you intend to travel to anyplace where hepatitis is viral . Lose any excess weight, and ensure you go for frequent check-ups
As the saying goes, prevention is better than cure and here are some measures you can take to preserve your liver health:
Poor nutrition rarely causes liver disease but excellent nutrition in the form of a balanced diet will enable the liver to perform its many various functions efficiently, resulting in better overall health. it can also help liver cells damaged by hepatitis viruses to regenerate, forming new liver cells.
But, whilst it is important to take vitamins and minerals, please note that an excess of Vitamin A is toxic to the liver and should be taken in moderation.
2. Limit intake of calories.
Excess calories in the form of carbohydrates can add to liver dysfunction and can cause fat deposits in the liver, contributing to fatty liver.
No more than 30% of a person’s total calories should come from fat because of the danger to the cardiovascular system. in order to estimate your daily calorie needs, you will need a minimum of 15 calories a day for each pound you weigh
3. Hold the alcohol
Liquor, beer and wine are hard for the liver to metabolise. the daily recommended alcohol intake is three units/drinks for men and two units/drinks for women.
As a general guide, one unit of alcohol translates to half a pint of ordinary strength beer, a small measure (25ml) of spirits or a standard measure (50ml) of fortified wine such as sherry or port.
Having three drinks or more per day should be avoided, as it may lead to alcoholic hepatitis and cirrhosis. People with liver disease should never drink alcohol at all. the same goes for individuals who are taking medication ? mixing alcohol with painkillers or other types of medications can be perilous to your liver.
In particular, the mixture of alcohol and acetaminophen (an ingredient in pain killers and cough medication) can cause sudden, severe hepatitis and even fatal liver failure. If you are not sure which medications to take in combination, please consult your doctor.
4. Beware “nutritional therapies”
Herbal treatments and alternative liver medicines should undergo rigorous scientific study before they can be recommended.
“Natural” or diet treatments and herbal remedies can be quite perilous. Plants of the Crotalaria, Senecio and Heliotopium families, as well as chaparral, mistletoe, skullcap, germander, comfrey, margosa oil, mate tea, Gordolobo yerba tea, pennyroyal, and Jin Blu Huan are all toxic to the liver.
Several scientific studies suggest that substances in milk thistle may protect the liver from harmful substances such as acetaminophen, which can cause liver hurt. it is also believed that milk thistle has antioxidant and anti-inflammatory properties, and it may help the liver repair itself by growing new cells.
5. stop smoking and stay away from toxic fumes and liquids.
Fumes from paint thinners, bug sprays, and other aerosol sprays are picked up by the tiny blood vessels in your lungs and carried to your liver where they are detoxified and discharged in your bile.
The amount and concentration of those chemicals should be controlled to prevent liver hurt. make certain you have excellent ventilation, use a mask, cover your skin, and wash off any chemicals you get on your skin with soap and water as soon as possible.
Hands should be washed with soap and water following bowel movements and before food preparation and consumption. this will help prevent the spread of hepatitis A.
Avoid sex with multiple partners or wear protection where unavoidable. Hepatitis B and C are transmitted through blood and body fluids. So use condoms and avoid sharing your personal items such as toothbrush, razor or manicure sets, especially if your partner may be suffering from a liver disease.
Vaccination for hepatitis A and B is available. an immunisation programme for hepatitis B has been in place for all children and adults since 1989 to prevent hepatitis B infection. it is essential to vaccinate newborns for hepatitis B as infections in this group will result in 90% chronic infection. there is no vaccination available for hepatitis C.
Chronic liver infection can lead to cirrhosis, where there are areas of scarring and liver cell regeneration within the liver.
Cirrhosis can lead to liver cancer, which is often diagnosed too late as few symptoms appear until it has reached an advanced stage. Signs and symptoms of liver cancer include right upper abdominal pain, jaundice (yellowing of the skin), abdominal swelling, weight loss, fatigue, simple bruising or bleeding.
Apart from surgery, for which most liver cancer patients are ineligible due to the advanced stages of the disease at time of diagnosis, there is currently an oral treatment that has been found to be effective in targeting the liver cancer cells specifically and can be used in patients who are unsuitable for surgery.
Sorafenib is an oral treatment available for the treatment of advanced liver cancer.
Keeping the liver healthy is essential to keeping your entire being healthy, so take excellent care of your liver, so that it can take care of you.
Source
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