August 11, 2010
Ghrelin is mostly known as a naturally occurring hormone that stimulates the appetite. However, new research demonstrates that this hormone might have therapeutic value to those with Hepatitis C.
by Nicole Cutler, L.Ac.
A hormone normally found in the stomach is proving to be of great interest to the Hepatitis C community. Known as an appetite-stimulating hormone, ghrelin is regarded with disdain by dieters and overweight individuals. Interestingly, ghrelin has demonstrated the ability to minimize one of the greatest hazards of the Hepatitis C virus - liver fibrosis.
About Ghrelin
Made in the stomach, ghrelin levels rise when people are hungry and they wane after a meal. People who get injections of this hormone gorge themselves, and those suffering from a rare disease that keeps ghrelin levels unusually high tend to be obese overeaters. Not surprisingly, researchers seeking to help people shed excessive weight have been actively trying to block ghrelin since its recognition in the late '90s. Of course, blocking an essential hormone carries unknown risks to our health. For people with chronic liver disease, researchers from Spain have uncovered a valid reason to treasure ghrelin - and be weary of blocking this curious hormone.
Fibrosis
One of the few organs that can regenerate, the liver has the remarkable ability to recover from minor injuries by healing itself. Unfortunately, this regenerative capacity can't keep up with diseases that cause significant liver damage. For those individuals living with chronic Hepatitis C (or any other kind of chronic liver disease), progressive scarring of liver tissue is a major concern.
Otherwise known as fibrosis, continual liver scarring can lead to cirrhosis - which ultimately renders the liver unable to function. Over 27,000 Americans die from cirrhosis annually, making it the country's third leading cause of death for people between the ages of 25 and 59, and the seventh leading cause of death overall. Needless to say, strategies to prevent fibrosis from worsening to cirrhosis are in high demand. Despite this need, there are currently no approved anti-fibrotic therapies on the market.
Ghrelin Fights Fibrosis
Published in the March 2010 edition of Hepatology, researchers from Spain's Hospital Clinic of Barcelona discovered that ghrelin has the potential of being a novel, anti-fibrotic therapy. According to Dr. Ramón Bataller, part of the team involved in the Barcelona study, "Our aim was to determine if recombinant ghrelin could regulate the formation of fibrous tissue associated with chronic liver damage."
The research team found the following:
· In animal models, ghrelin reduced the amount of fibrogenic cells by 25 percent.
· Participants with chronic Hepatitis C and alcoholic hepatitis had significantly lower ghrelin levels than did healthy individuals.
The researchers concluded that ghrelin inhibits the development of liver fibrosis in both animals and humans.
Insulin Resistance
The link connecting this appetite-stimulating hormone to its protection against liver fibrosis remains unclear. However, research from 2003 may be on the right track. According to an Italian study published in the Journal of Clinical Endocrinology & Metabolism, insulin resistance may be the bridge between ghrelin levels and liver damage. In individuals with NAFLD (non-alcoholic fatty liver disease), insulin resistance is believed to be relatively independent of obesity. After evaluating subjects with NAFLD, the Italian researchers found that insulin resistance plays a primary role in controlling ghrelin levels.
Insulin resistance is a decreased ability to respond to the effects of insulin, a hormone that helps transport glucose into the body's cells for making energy. Since cells need glucose to survive, the body compensates for insulin resistance by producing additional amounts of this hormone. Although not a disease or specific diagnosis, insulin resistance has a ripple effect on the body and is associated with heart disease, polycystic ovarian syndrome, Type 2 diabetes, obesity and NAFLD.
Thanks to Bataller's team, the connection between ghrelin and fibrosis could help prevent liver scarring in people who are most prone. Future studies are likely going to take insulin resistance into consideration while determining the safety and efficacy of ghrelin in people with chronic liver disease. If this hormone continues to prove its value to the liver, efforts to block ghrelin for weight loss purposes will likely lose steam. On the other hand, those with Hepatitis C could benefit by finally having a therapeutic option to prevent the progression of liver scarring.
References:
http://cordis.europa.eu/fetch?CALLER=EN_NEWS&ACTION=D&SESSION=&RCN=31823, Body's own hormone may be liver disease's worst foe, Retrieved March 15, 2010, CORDIS Services, 2010.
http://jcem.endojournals.org/cgi/content/abstract/88/12/5674, Low Ghrelin Concentrations in Nonalcoholic Fatty Liver Disease Are Related to Insulin Resistance, G.Marchesini, et al, Retrieved March 19, 2010, Journal of Clinical Endocrinology & Metabolism, August 2003.
http://www.cbsnews.com/stories/2003/03/11/60II/main543614.shtml, The Hunger Hormone, Carol Kopp, Retrieved March 15, 2010, CBS Interactive Inc., 2010.
http://www.eurekalert.org/pub_releases/2010-03/w-gml022510.php, Ghrelin mitigates liver fibrosis in animal models; regulates human fibrosis, Retrieved March 15, 2010, EurekAlert, 2010.
http://www.healthsquare.com/fgpd/fg4ch20.htm, Dealing with Liver Disease, Retrieved March 19, 2010, The HealthCentral Network, Inc., 2010.
http://www.labtestsonline.org/understanding/conditions/insulin_resistance.html, Insulin Resistance, Retrieved March 19, 2010, American Association for Clinical Chemistry, 2010.
http://www.ncbi.nlm.nih.gov/pubmed/20077562, Ghrelin attenuates hepatocellular injury and liver fibrogenesis in rodents and influences fibrosis progression in humans, Moreno M, et al, Retrieved March 15, 2010, Hepatology, March 2010.
http://www.newscientist.com/article/dn13845-stomach-hormone-turns-hungry-people-into-junkies.html, Stomach hormone turns hungry people into junkies, Ewen Callaway, Retrieved March 18, 2010, Reed Business Information Ltd, 2010.
Source
August 11, 2010
Infergen Gives Hepatitis C Patients An Extra Chance
ALEXANDRIA, Va. (WUSA) -- Approximately 50 percent of chronic hepatitis C patients do not respond to their initial course of therapy, according to Bruce R. Bacon M.D. of Saint Louis University School of Medicine.
Dr. Bacon is the lead investigator of the registration trial for Infergen, a new treatment for Hepatitis C patients that recieved FDA approval last month.
Dr. Bacon says, "The FDA's recognition of the expanded label allows patients failing therapy a safe and efficacious retreatment strategy."
This is good news for 59 year-old Hubert "Shep" Sheppard. Shep is a physically active man who bikes 60 miles a week and used to jump out of airplanes as a paratrooper. Now he is a private detective.
However, the one challenge that could have cost Shep his vitality, even his life, was Hepatitis C.
Shep says, "I have no idea where I got it. I was totally shocked I had this disease."
He adds, "I probably had it for a while, and had no indications of it."
In Shep's case, the chronic infection was attacking his liver. His first round of treatment wasn't enough to clear it.
Shep says, "There's some difference in African-Americans in that we don't respond well to some treatment."
Dr. Jonathan McCone of Alexandria, Virginia says Hepatitis C can be a silent killer.
Dr. McCone says, "Its basically not a sexually transmitted disease. Its not transmitted by kissing or sneezing in somebody's face, or breathing the same air. It's a blood-to-blood disease."
He adds, "One can end up with advanced liver disease, cirrhosis, liver cancer, and the need for liver transplant."
Fortunately Shep was able to take advantage of Infergen, given daily with ribivirin pills, it delivers a one-two punch to the virus.
The down-side, the regimen that lasts for months also delivers a whallop of side effects from extreme fatigue to weight and hair loss, and anemia.
But Shep says he approached it with a military mind-set.
Shep says, "I just saw it as a personal combat between me and this disease, and I just thought that one of us is going to be carried out in a box and its not going to be me."
Shep tested clean of the virus last year, and is now considered cured.
There is no vaccine for Hepatitis C, like there is for A and B.
Source
Portuguese scientists discover an extraordinary new type of white blood cells
11 August 2010
Ciência Viva - Agência Nacional para a Cultura Científica e Tecnológica
After a transplant – and to assure that the new organ is not rejected - patients are put on life-long therapy to suppress their immune system (IS), which, nevertheless, needs to be left intact enough to be able to defend the body against all kinds of disease. A tricky balance as the many rejected organs attest. But a discovery by Maria Monteiro and Luis Graça, two Portuguese scientists, could change all this, at least for the liver. Their work, just out in the Journal of Immunology (1), describes how they found a new type of white blood cell – baptised NKTreg (reg from regulatory) – that, once activated, migrate into the liver and suppress any immune response in its vicinity. What is most remarkable is that the immune system elsewhere is left intact. And the implications do not end in better liver transplants as, once these cells create an “immune tolerant organ”, we can graft any type of tissue or express any gene that the body might need into it, knowing that it would be safe from the IS. The potential of the discovery is such that a patent by Monteiro and Graça for the production and therapeutic use of NKTreg cells in humans has already been accepted.
Controlling an unwanted immune response, whether to stop organ rejection after a transplant or for the treatment of autoimmune diseases – in which an abnormal IS attacks the own body- can be tricky. At the moment there are two types of approaches: general immunosuppression or deletion of entire “arms” of the IS. Both methods require a difficult equilibrium between stopping the damaging immune response while allowing patients to remain immuno-competent, and both carry potentially serious side effects. Most recent therapies fall in the second approach and work by deleting a particular type of cell or protein (an “arm” of the IS) at the core of the immune response we want to stop. While these methods can be extraordinarily effective – thousand of patients had their lives changed by them – unfortunately, they do not seem to work for long, probably because the IS adapts and brings other cells and proteins to do the job of the lost “arm”. While this is not a problem for pharmaceutical companies that can go on developing new and even more expensive drugs, to patients it means a life of constant uncertainty and many potential problems– will the next new drug be effective, will it stop working, will then be yet another drug ready, what about side effects?
The truth is that these kinds of approaches are a far cry from a 21st century medicine with emphasis in personalised and very specific therapies, and it is crucial that new and better treatments are found.
It is in this context that a family of white blood cells called regulatory T cells has been hailed as “next big thing” - shown to suppress immune responses and part of the body’s mechanisms to stop undesired immune responses, these cells could be key to more specific treatments while are also less prone to be “overridden” by the body control mechanisms. And in fact, human trials for their use in transplantation are already under way although much work needs to be done. But meanwhile another family of white blood cells - called NKT cells - has also came to the attention of scientists when shown to protect mice from several autoimmune diseases, including diabetes and autoimmune encephalomyelitis (EAE) - the animal equivalent of multiple sclerosis
To try to understand better the potential of NKT cells Marta Monteiro, Luis Graça and colleagues at the Instituto de Medicina Molecular, University of Lisbon and the Instituto Gulbenkian de Ciência in Oeiras, Portugal looked at mice protected from EAE using NKT cells (like shown by others). In these mice they analysed the lymph nodes that drain the brain – the logic being that since EAE affects the brain, protective cells should be found in the lymph nodes directly linked to it. To their surprise they discover a total new population of NKT cells that expressed Foxp3 – a marker for regulatory T cell, linked to these cells immunosuppressive capabilities. When these new NKT cells were studied in laboratory they revealed several other similarities – not only they share many other receptors of regulatory T cells but, like them, both Foxp3 and their suppressive abilities are triggered by a protein called TGFbeta – leading Monteiro and Graça to name them NKTreg cells.
But how do these cells act when in the body? To answer this question, and after activating NKT cells to become NKTreg (so Foxp3 positive) and tag them with a fluorescent marker so they could be easily traced, Monteiro and Graça injected the (suppressive) cells back into mice. Remarkably these cells homed straight to the liver – in this they are very different from regulatory T cells that move into all lymphoid organs; spleen, lymph nodes, etc - suggesting that in normal conditions NKTreg cells could perform some immunosuppressive role in this organ.
The implications of this discovery are important and many. In liver transplants although success rate has increased substantially the odds that the organ will survive up to 15 years are still only around 58%, with as many as 10-15% of patients experiencing organ rejection before the end of the first year. Not only that, but current immunosuppression therapies are costly and affect patients’ life expectancy by putting them at higher risk of cancer and mortal infections. NKTreg cells – if proved to function in the same way in humans, and Monteiro has already shown that we at least have them - might be the answer to these problems.
As Luis Graça explains “the liver is already the transplanted organ with higher chances of success due to its unique characteristics, by using these new cells we might be able to achieve almost 100% organ acceptance and this without touching the remaining IS, what is remarkable. Patients might be able to survive with only a minimum dose of other immunsuppressors”.
But there are other major implications to be able to create a “bubble of tolerance” within the body. Many diseases caused by the absence of a molecule or metabolic tissue are being treated with therapies that insert replacements into the body. The problem is that the IS soon or later detects these new “parts” and attacks them. The liver is already a place where the immune system seems to be less vigilant - probably so it is not over-activated all the time by the food and microbial molecules that come through the digestive system – add NKTreg cells to this organ and it can became the perfect place to hide anything from the IS.
And in fact, at the moment, some diabetic patients – that lack insulin to metabolise sugars – already have insulin-producing grafts on their liver, while some gene therapies, for example for the production of clothing factors in haemophilia (a disease where patients can not coagulate their blood) are already being expressed in the organ. NKTreg, if they work in the same way in humans as in mice, can radically improve the chances of success of these and other therapies. The potential of being able to create a contained area of immunosuppression within the body without touching the remaining immune responses elsewhere in the body, is immense. But first we need to see if and how NKTreg cells work in humans and that is what Monteiro and Graça plan to do next.
Piece by:Catarina Amorim
http://www.jimmunol.org/cgi/content/abstract/jimmunol.1000359v1
Source
Ciência Viva - Agência Nacional para a Cultura Científica e Tecnológica
After a transplant – and to assure that the new organ is not rejected - patients are put on life-long therapy to suppress their immune system (IS), which, nevertheless, needs to be left intact enough to be able to defend the body against all kinds of disease. A tricky balance as the many rejected organs attest. But a discovery by Maria Monteiro and Luis Graça, two Portuguese scientists, could change all this, at least for the liver. Their work, just out in the Journal of Immunology (1), describes how they found a new type of white blood cell – baptised NKTreg (reg from regulatory) – that, once activated, migrate into the liver and suppress any immune response in its vicinity. What is most remarkable is that the immune system elsewhere is left intact. And the implications do not end in better liver transplants as, once these cells create an “immune tolerant organ”, we can graft any type of tissue or express any gene that the body might need into it, knowing that it would be safe from the IS. The potential of the discovery is such that a patent by Monteiro and Graça for the production and therapeutic use of NKTreg cells in humans has already been accepted.
Controlling an unwanted immune response, whether to stop organ rejection after a transplant or for the treatment of autoimmune diseases – in which an abnormal IS attacks the own body- can be tricky. At the moment there are two types of approaches: general immunosuppression or deletion of entire “arms” of the IS. Both methods require a difficult equilibrium between stopping the damaging immune response while allowing patients to remain immuno-competent, and both carry potentially serious side effects. Most recent therapies fall in the second approach and work by deleting a particular type of cell or protein (an “arm” of the IS) at the core of the immune response we want to stop. While these methods can be extraordinarily effective – thousand of patients had their lives changed by them – unfortunately, they do not seem to work for long, probably because the IS adapts and brings other cells and proteins to do the job of the lost “arm”. While this is not a problem for pharmaceutical companies that can go on developing new and even more expensive drugs, to patients it means a life of constant uncertainty and many potential problems– will the next new drug be effective, will it stop working, will then be yet another drug ready, what about side effects?
The truth is that these kinds of approaches are a far cry from a 21st century medicine with emphasis in personalised and very specific therapies, and it is crucial that new and better treatments are found.
It is in this context that a family of white blood cells called regulatory T cells has been hailed as “next big thing” - shown to suppress immune responses and part of the body’s mechanisms to stop undesired immune responses, these cells could be key to more specific treatments while are also less prone to be “overridden” by the body control mechanisms. And in fact, human trials for their use in transplantation are already under way although much work needs to be done. But meanwhile another family of white blood cells - called NKT cells - has also came to the attention of scientists when shown to protect mice from several autoimmune diseases, including diabetes and autoimmune encephalomyelitis (EAE) - the animal equivalent of multiple sclerosis
To try to understand better the potential of NKT cells Marta Monteiro, Luis Graça and colleagues at the Instituto de Medicina Molecular, University of Lisbon and the Instituto Gulbenkian de Ciência in Oeiras, Portugal looked at mice protected from EAE using NKT cells (like shown by others). In these mice they analysed the lymph nodes that drain the brain – the logic being that since EAE affects the brain, protective cells should be found in the lymph nodes directly linked to it. To their surprise they discover a total new population of NKT cells that expressed Foxp3 – a marker for regulatory T cell, linked to these cells immunosuppressive capabilities. When these new NKT cells were studied in laboratory they revealed several other similarities – not only they share many other receptors of regulatory T cells but, like them, both Foxp3 and their suppressive abilities are triggered by a protein called TGFbeta – leading Monteiro and Graça to name them NKTreg cells.
But how do these cells act when in the body? To answer this question, and after activating NKT cells to become NKTreg (so Foxp3 positive) and tag them with a fluorescent marker so they could be easily traced, Monteiro and Graça injected the (suppressive) cells back into mice. Remarkably these cells homed straight to the liver – in this they are very different from regulatory T cells that move into all lymphoid organs; spleen, lymph nodes, etc - suggesting that in normal conditions NKTreg cells could perform some immunosuppressive role in this organ.
The implications of this discovery are important and many. In liver transplants although success rate has increased substantially the odds that the organ will survive up to 15 years are still only around 58%, with as many as 10-15% of patients experiencing organ rejection before the end of the first year. Not only that, but current immunosuppression therapies are costly and affect patients’ life expectancy by putting them at higher risk of cancer and mortal infections. NKTreg cells – if proved to function in the same way in humans, and Monteiro has already shown that we at least have them - might be the answer to these problems.
As Luis Graça explains “the liver is already the transplanted organ with higher chances of success due to its unique characteristics, by using these new cells we might be able to achieve almost 100% organ acceptance and this without touching the remaining IS, what is remarkable. Patients might be able to survive with only a minimum dose of other immunsuppressors”.
But there are other major implications to be able to create a “bubble of tolerance” within the body. Many diseases caused by the absence of a molecule or metabolic tissue are being treated with therapies that insert replacements into the body. The problem is that the IS soon or later detects these new “parts” and attacks them. The liver is already a place where the immune system seems to be less vigilant - probably so it is not over-activated all the time by the food and microbial molecules that come through the digestive system – add NKTreg cells to this organ and it can became the perfect place to hide anything from the IS.
And in fact, at the moment, some diabetic patients – that lack insulin to metabolise sugars – already have insulin-producing grafts on their liver, while some gene therapies, for example for the production of clothing factors in haemophilia (a disease where patients can not coagulate their blood) are already being expressed in the organ. NKTreg, if they work in the same way in humans as in mice, can radically improve the chances of success of these and other therapies. The potential of being able to create a contained area of immunosuppression within the body without touching the remaining immune responses elsewhere in the body, is immense. But first we need to see if and how NKTreg cells work in humans and that is what Monteiro and Graça plan to do next.
Piece by:Catarina Amorim
http://www.jimmunol.org/cgi/content/abstract/jimmunol.1000359v1
Source
Highest Rates Of Hepatitis C Virus Transmission Found In Egypt
Article Date: 11 Aug 2010 - 1:00 PDT
The Arab Republic of Egypt has the highest rates of new hepatitis C virus (HCV) infection in the world, according to a new study published in the prestigious Proceedings of the National Academy of Sciences. The study also estimates more than 500,000 new HCV infections occur in Egypt every year, likely signaling an epidemic in a country of more than 77 million people. This high rate of HCV transmission may be due to the lack of sufficient standard safety precautions in medical and dental facilities, the authors suggest.
"Nearly 7 out of every 1,000 Egyptians acquire HCV infections every year, suggesting intense ongoing transmission. This is the highest level of HCV transmission ever recorded at a national level for a blood borne infectious disease transmitted parenterally, that is, by use of non-sterile medical instruments," said Dr. F. DeWolfe Miller, lead author of this study and professor of epidemiology at the Department of Tropical Medicine and Medical Microbiology and Pharmacology at the University of Hawaii.
Although the high prevalence of hepatitis C in Egypt has been well established for many years, and linked in part to limited safety measures during anti-bilharzia campaigns, published estimates of prevalence from different Egyptian communities failed to provide a nationwide picture of the magnitude of ongoing HCV infection transmission. To estimate the rate of new HCV cases of infection in Egypt, the authors of the study performed epidemiologic modeling of data from a range of studies, including a 2008 national HCV survey with a representative sample and well-documented study design.
"The study opened our eyes to a disease burden similar in scale and challenge to the HIV problem in sub-Saharan Africa: Millions of cases of an infection for which there is no vaccine, no effective treatment, and where case management is so expensive that it is beyond the reach of most patients," said Dr. Laith J. Abu-Raddad, co-author of the study and assistant professor of public health at the Infectious Disease Epidemiology Group at the Weill Cornell Medical College-Qatar.
The study necessitates not only further analysis of HCV transmission in Egypt but also justifies the immediate increase of resources to strengthen public health measures aimed at reducing the transmission of HCV in clinical and non-clinical settings, according to the authors. Failure to address this problem will result in a massive disease burden in the nation in terms of HCV infection complications, including active liver disease, liver failure, or liver cancer.
"There is only one way to deal with the HCV challenge in this country: HCV prevention," warned Dr. Miller. "Effective and stronger HCV prevention programs are urgently needed in Egypt. Failure to act could swamp the public health system over the coming decades with millions of cases of HCV disease complications with an economic and social cost that this nation does not have the means to confront."
Key scientific findings of the study
• Nearly 7 out of each 1,000 Egyptians acquire HCV infection every year for a total of 537,000 new HCV infections every year. This is by far the largest ever recorded rate of occurrence of HCV at a national level of all countries in the world.
• One in every 10 Egyptians is a carrier of the HCV infection, which means that there are at least 4,459,000 persons infected with HCV who are infectious to others. This is the largest reservoir of HCV infection in the world.
• Contrary to the widely-held perception that this rate of occurrence reflects merely the limited safety measures during anti-bilharzia campaigns, HCV incidence likely continues at alarming levels due to limitations in the implementation and enforcement of stringent standard precautions in public and private medical and dental facilities.
F. DeWolfe Miller, PhD (Lead Author)
Department of Tropical Medicine and Medical Microbiology and Pharmacology
University of Hawaii
Honolulu, HI, USA
Laith Abu-Raddad, PhD (Co-Author)
Director of Epidemiology, Biostatistics and Biomathematics Research Core
Assistant Professor in Public Health
Weill Cornell Medical College - Qatar
Doha, Qatar
Source:
Weill Cornell
Source
The Arab Republic of Egypt has the highest rates of new hepatitis C virus (HCV) infection in the world, according to a new study published in the prestigious Proceedings of the National Academy of Sciences. The study also estimates more than 500,000 new HCV infections occur in Egypt every year, likely signaling an epidemic in a country of more than 77 million people. This high rate of HCV transmission may be due to the lack of sufficient standard safety precautions in medical and dental facilities, the authors suggest.
"Nearly 7 out of every 1,000 Egyptians acquire HCV infections every year, suggesting intense ongoing transmission. This is the highest level of HCV transmission ever recorded at a national level for a blood borne infectious disease transmitted parenterally, that is, by use of non-sterile medical instruments," said Dr. F. DeWolfe Miller, lead author of this study and professor of epidemiology at the Department of Tropical Medicine and Medical Microbiology and Pharmacology at the University of Hawaii.
Although the high prevalence of hepatitis C in Egypt has been well established for many years, and linked in part to limited safety measures during anti-bilharzia campaigns, published estimates of prevalence from different Egyptian communities failed to provide a nationwide picture of the magnitude of ongoing HCV infection transmission. To estimate the rate of new HCV cases of infection in Egypt, the authors of the study performed epidemiologic modeling of data from a range of studies, including a 2008 national HCV survey with a representative sample and well-documented study design.
"The study opened our eyes to a disease burden similar in scale and challenge to the HIV problem in sub-Saharan Africa: Millions of cases of an infection for which there is no vaccine, no effective treatment, and where case management is so expensive that it is beyond the reach of most patients," said Dr. Laith J. Abu-Raddad, co-author of the study and assistant professor of public health at the Infectious Disease Epidemiology Group at the Weill Cornell Medical College-Qatar.
The study necessitates not only further analysis of HCV transmission in Egypt but also justifies the immediate increase of resources to strengthen public health measures aimed at reducing the transmission of HCV in clinical and non-clinical settings, according to the authors. Failure to address this problem will result in a massive disease burden in the nation in terms of HCV infection complications, including active liver disease, liver failure, or liver cancer.
"There is only one way to deal with the HCV challenge in this country: HCV prevention," warned Dr. Miller. "Effective and stronger HCV prevention programs are urgently needed in Egypt. Failure to act could swamp the public health system over the coming decades with millions of cases of HCV disease complications with an economic and social cost that this nation does not have the means to confront."
Key scientific findings of the study
• Nearly 7 out of each 1,000 Egyptians acquire HCV infection every year for a total of 537,000 new HCV infections every year. This is by far the largest ever recorded rate of occurrence of HCV at a national level of all countries in the world.
• One in every 10 Egyptians is a carrier of the HCV infection, which means that there are at least 4,459,000 persons infected with HCV who are infectious to others. This is the largest reservoir of HCV infection in the world.
• Contrary to the widely-held perception that this rate of occurrence reflects merely the limited safety measures during anti-bilharzia campaigns, HCV incidence likely continues at alarming levels due to limitations in the implementation and enforcement of stringent standard precautions in public and private medical and dental facilities.
F. DeWolfe Miller, PhD (Lead Author)
Department of Tropical Medicine and Medical Microbiology and Pharmacology
University of Hawaii
Honolulu, HI, USA
Laith Abu-Raddad, PhD (Co-Author)
Director of Epidemiology, Biostatistics and Biomathematics Research Core
Assistant Professor in Public Health
Weill Cornell Medical College - Qatar
Doha, Qatar
Source:
Weill Cornell
Source
Transplant Patients Can Benefit From Loved Ones' Care
August 10, 2010, 16:00 EST
Caregiving by those with emotional connection lessens anxiety, depression after surgery, study found
TUESDAY, Aug. 10 (HealthDay News) -- Transplant patients who have a close emotional connection with family members or other caregivers experience less depression and anxiety after surgery, new research has found.
The study included 74 liver transplant patients and their primary caregivers who were surveyed before surgery and six months after transplantation. Caregivers were asked to rate how close they felt to the patient, and the sample was divided into a group whose caregivers reported the most closeness and a group whose caregivers reported the least.
Symptoms of depression and anxiety decreased among the patients after their liver transplant, but the improvements weren't as significant for those with an emotionally distant caregiver, according to the researchers from the Henry Ford Hospital in Detroit.
"If you live with someone who loves you, the quality of care they provide may be much better, they may be more encouraging, you may want to please them and recuperate faster so you can spend quality time with them," lead author Anne Eshelman, of the Henry Ford Health System Behavioral Health Services, said in a hospital news release.
"Caregivers who are not close may provide the basic requirements, but don't help give someone a reason to live and look to the future," she added.
The study findings also indicated that emotional closeness was critical in male patients, but less so for women (although the researchers pointed out that interpretation of the results was difficult due to the small sample size).
"Men who had an adequate number of support people, but did not have close support, were still depressed and anxious at follow-up, compared to those who had closer support," Eshelman said. "Other literature shows that women have wider support, more friends and family they are connected to than men, and if the primary support person is not that close, they probably rely on the other people such as girlfriends."
The study was scheduled for presentation Aug. 6 at the International Congress of Behavioral Medicine in Washington, D.C.
More information
The American Society of Transplantation has more about health after transplantation.
-- Robert Preidt
SOURCE: Henry Ford Hospital, news release, Aug. 6, 2010
Source
Caregiving by those with emotional connection lessens anxiety, depression after surgery, study found
TUESDAY, Aug. 10 (HealthDay News) -- Transplant patients who have a close emotional connection with family members or other caregivers experience less depression and anxiety after surgery, new research has found.
The study included 74 liver transplant patients and their primary caregivers who were surveyed before surgery and six months after transplantation. Caregivers were asked to rate how close they felt to the patient, and the sample was divided into a group whose caregivers reported the most closeness and a group whose caregivers reported the least.
Symptoms of depression and anxiety decreased among the patients after their liver transplant, but the improvements weren't as significant for those with an emotionally distant caregiver, according to the researchers from the Henry Ford Hospital in Detroit.
"If you live with someone who loves you, the quality of care they provide may be much better, they may be more encouraging, you may want to please them and recuperate faster so you can spend quality time with them," lead author Anne Eshelman, of the Henry Ford Health System Behavioral Health Services, said in a hospital news release.
"Caregivers who are not close may provide the basic requirements, but don't help give someone a reason to live and look to the future," she added.
The study findings also indicated that emotional closeness was critical in male patients, but less so for women (although the researchers pointed out that interpretation of the results was difficult due to the small sample size).
"Men who had an adequate number of support people, but did not have close support, were still depressed and anxious at follow-up, compared to those who had closer support," Eshelman said. "Other literature shows that women have wider support, more friends and family they are connected to than men, and if the primary support person is not that close, they probably rely on the other people such as girlfriends."
The study was scheduled for presentation Aug. 6 at the International Congress of Behavioral Medicine in Washington, D.C.
More information
The American Society of Transplantation has more about health after transplantation.
-- Robert Preidt
SOURCE: Henry Ford Hospital, news release, Aug. 6, 2010
Source
Love the Glove: Glove Use in Hospitals Appears to Cut Risk of Needlestick Injury
August 10, 2010
Wearing gloves reduces the risk of injury by needles and sharp medical devices, or sharps injuries, by about 66 percent, according to a new study by Canadian and U.S. researchers. Double-gloving brought the risk down further, by about 80 percent.
The study involved 636 health care workers from 13 medical centers in the United States or Canada who presented to employee health clinics after a sharps injury. Of the workers, 195 were scrubbed in an operating room or procedure suite when injured, and 441 were non-scrubbed and injured elsewhere. The latter were more likely to be gloved when treating patients who were perceived to have a high risk of HIV, hepatitis B or hepatitis C.
In case-crossover analyses, gloves reduced injury risk (incidence rate ratio [IRR] 0.33 [95 percent CI, 0.22-0.50]. Among scrubbed individuals, "involvement in an orthopedic procedure was associated with double-gloving at injury (adjusted odds ratio, 13.7 [95 percent CI, 4.55-41.3]); this gloving practice was associated with decreased injury risk (IRR, 0.20 [95 percent CI, 0.10-0.42])."
"Gloving actually reduces the likelihood that a needle will go through your skin and inoculate you with blood," said senior study author Dr. David Fisman, an epidemiologist and researcher with the University of Toronto and Toronto's Hospital for Sick Children. In passing through the latex or vinyl membrane, some of the blood from the needle will be removed, reducing the inoculum or potentially infected blood, he explained.
Yet despite this, "There are kind of these weird beliefs about if you glove then you get clumsier and if you get clumsier, then you stick yourself," Fisman said.
The full report, "Use of Gloves and Reduction of Risk of Injury Caused by Needles or Sharp Medical Devices in Healthcare Workers: Results From a Case-Crossover Study," was published in Infection Control & Hospital Epidemiology (2010;31:908-917).
Source
Wearing gloves reduces the risk of injury by needles and sharp medical devices, or sharps injuries, by about 66 percent, according to a new study by Canadian and U.S. researchers. Double-gloving brought the risk down further, by about 80 percent.
The study involved 636 health care workers from 13 medical centers in the United States or Canada who presented to employee health clinics after a sharps injury. Of the workers, 195 were scrubbed in an operating room or procedure suite when injured, and 441 were non-scrubbed and injured elsewhere. The latter were more likely to be gloved when treating patients who were perceived to have a high risk of HIV, hepatitis B or hepatitis C.
In case-crossover analyses, gloves reduced injury risk (incidence rate ratio [IRR] 0.33 [95 percent CI, 0.22-0.50]. Among scrubbed individuals, "involvement in an orthopedic procedure was associated with double-gloving at injury (adjusted odds ratio, 13.7 [95 percent CI, 4.55-41.3]); this gloving practice was associated with decreased injury risk (IRR, 0.20 [95 percent CI, 0.10-0.42])."
"Gloving actually reduces the likelihood that a needle will go through your skin and inoculate you with blood," said senior study author Dr. David Fisman, an epidemiologist and researcher with the University of Toronto and Toronto's Hospital for Sick Children. In passing through the latex or vinyl membrane, some of the blood from the needle will be removed, reducing the inoculum or potentially infected blood, he explained.
Yet despite this, "There are kind of these weird beliefs about if you glove then you get clumsier and if you get clumsier, then you stick yourself," Fisman said.
The full report, "Use of Gloves and Reduction of Risk of Injury Caused by Needles or Sharp Medical Devices in Healthcare Workers: Results From a Case-Crossover Study," was published in Infection Control & Hospital Epidemiology (2010;31:908-917).
Source
For Lilly, it's a big one that got away
J.K. Wall August 11, 2010
Mark this one in Eli Lilly and Co.’s “Oops!” category.
An experimental medicine for hepatitis C that Lilly helped identify and develop is now on the cusp of market approval. According to an article in Xconomy.com, a biotech trade publication, some analysts are predicting as much as $2 billion in annual U.S. sales after the drug's expected market launch in 2011.
But in December 2002, Lilly sold back its rights to the drug, telaprevir, to its inventor, Massachusetts-based Vertex Pharmaceuticals Inc
Any revenue from telaprevir, which would have been split with Vertex, would have been awfully nice right now for Lilly. The Indianapolis-based drugmaker will watch patents expire on its cancer drug Gemzar in November and its antipsyhotic blockbuster Zyprexa a year later.
Cheaper generic copies will steal the lion’s share of those two drugs’ $6 billion in annual sales.
“It’s a decision that Lilly has to regret,” Xconomy.com reporter Ryan McBride wrote about telaprevir, which proved effective for three out of four patients with hepatitis C, a chronic liver disease, during a large Phase 3 clinical trial.
McBride cited a former Vertex executive who said telaprevir’s champions within Lilly were shuffled off the program, and it subsequently fell down Lilly’s priority list.
Vertex later signed co-development deals with New Jersey-based Johnson & Johnson and Japan-based Mitsubishi Tanabe, according to Xconomy.com.
“At Lilly, we regularly review our portfolio and sometimes re-prioritize assets based on resource availability,” Lilly spokesman Mark Taylor said in a statement. “Although we may decide to discontinue internal development of a molecule, we many times try to find ways to allow partner companies to continue the development. We believe this is in the best interest of the patients who may ultimately benefit if a new medicine makes it to the market."
Source
Mark this one in Eli Lilly and Co.’s “Oops!” category.
An experimental medicine for hepatitis C that Lilly helped identify and develop is now on the cusp of market approval. According to an article in Xconomy.com, a biotech trade publication, some analysts are predicting as much as $2 billion in annual U.S. sales after the drug's expected market launch in 2011.
But in December 2002, Lilly sold back its rights to the drug, telaprevir, to its inventor, Massachusetts-based Vertex Pharmaceuticals Inc
Any revenue from telaprevir, which would have been split with Vertex, would have been awfully nice right now for Lilly. The Indianapolis-based drugmaker will watch patents expire on its cancer drug Gemzar in November and its antipsyhotic blockbuster Zyprexa a year later.
Cheaper generic copies will steal the lion’s share of those two drugs’ $6 billion in annual sales.
“It’s a decision that Lilly has to regret,” Xconomy.com reporter Ryan McBride wrote about telaprevir, which proved effective for three out of four patients with hepatitis C, a chronic liver disease, during a large Phase 3 clinical trial.
McBride cited a former Vertex executive who said telaprevir’s champions within Lilly were shuffled off the program, and it subsequently fell down Lilly’s priority list.
Vertex later signed co-development deals with New Jersey-based Johnson & Johnson and Japan-based Mitsubishi Tanabe, according to Xconomy.com.
“At Lilly, we regularly review our portfolio and sometimes re-prioritize assets based on resource availability,” Lilly spokesman Mark Taylor said in a statement. “Although we may decide to discontinue internal development of a molecule, we many times try to find ways to allow partner companies to continue the development. We believe this is in the best interest of the patients who may ultimately benefit if a new medicine makes it to the market."
Source
August 10, 2010
KERRY & HONDA: Disrupting a deadly disease
Hepatitis defense can save thousands of lives a year
By Sen. John Kerry and Rep. Michael M. Honda
The Washington Times
6:54 p.m., Tuesday, August 10, 2010
A silent killer is loose in America. It contributes to the death of 15,000 Americans a year and threatens the health of 5.3 million more. It is more common than HIV/AIDS. It is the leading cause of liver cancer - a cancer that is on the rise and continues to be a fatal and costly disease. Yet it remains unrecognized as a serious threat to public health.
This silent killer is viral hepatitis. Most people don't even know they have it until years later, when it causes cancer or liver disease. But we can help avoid such needless tragedies with prevention and surveillance programs and by educating Americans on the pervasive nature of hepatitis B and hepatitis C.
A first step is to change the way viral hepatitis is diagnosed and treated, and that is why we have introduced legislation in the Senate and the House to provide almost $600 million over the next few years to treat this deadly epidemic. Our legislation will make our health care system more efficient. More important, it will save lives.
The bills we have introduced closely mirror the recommendations in a recent report from the Institute of Medicine (IOM), "Hepatitis and Liver Cancer," which calls for a national strategy to prevent and control hepatitis B and C.
The report concludes that the current approach is not working: Americans at risk for hepatitis or living with it do not know it, and health providers are not screening for it. That should come as no surprise because there is no federal funding of core public health services for viral hepatitis. Nor is there any federally funded chronic hepatitis B and C surveillance system.
Not surprisingly, the IOM report recommends increased information and awareness about chronic viral hepatitis among health care providers, social service providers and the public; improved surveillance for hepatitis B and hepatitis C; and better integration of viral hepatitis services.
Our call for a national strategy is not unlike IOM's. Specifically, our bills increase interagency coordination between the Centers for Disease Control and Prevention (CDC), the National Institutes of Health (NIH), the National Cancer Institute (NCI), the Health Resources and Services Administration (HRSA), the Substance Abuse and Mental Health Services Administration (SAMHSA), the Agency for Healthcare Research and Quality (AHRQ) and the Department of Veterans Affairs (VA).
It sets up programs to improve understanding of hepatitis B and C and requires the CDC to integrate them into existing immunization, prevention and control programs and support counseling. It also expands current vaccination programs and establishes a national chronic and acute hepatitis B and C surveillance program to identify incidence and prevalence in viral hepatitis and liver cancer.
Hepatitis B is 100 times more infectious than HIV and, left untreated, can cause liver disease, liver cancer and premature death decades after infection. About 2 billion people worldwide have been infected with hepatitis B, and about 170 million people are chronically infected with hepatitis C. Tragically, two-thirds of those infected, on average, are unaware of their status, which increases the chance of spreading the disease.
We cannot afford to be silent anymore. Our fellow citizens are dying daily because our nation lacks a comprehensive prevention, education and medical management program. Each year, about 15,000 people die from liver cancer or liver diseases related to hepatitis B and hepatitis C. That's more than 40 deaths every day.
Beyond the tragic and preventable loss of human life, there is the economic cost. Although the costs of education, research and treatment are not trivial, they are substantially less than the annual health care cost attributable to viral hepatitis in the United States.
Without effective prevention and vaccination methods, chronic hepatitis B and C are expected to cost our country billions of dollars in the coming years. The baby-boomer population is estimated to account for two out of every three cases of chronic hepatitis C. As these Americans age and enter into Medicare, they are likely to develop complications and require expensive medical interventions. In the next decade, the costs of hepatitis C to commercial insurance and Medicare will more than double, and within 20 years, Medicare costs will increase fivefold. Projecting further out, over the next 20 years, total medical costs for patients with hepatitis C infection could increase more than 2.5 times - from $30 billion to more than $85 billion.
Contrast the costs for early detection and intervention with the costs for treatment post-infection. The costs for hepatitis B vaccinations vary but range from $75 to $165, whereas treatment can cost up to $16,000 per year. Screening for hepatitis C is also relatively inexpensive compared to treatment, which can cost up to $25,000 per year. Untreated, these infections will develop into liver disease that can cost up to $110,000 per hospital admission.
Moreover, the United States is entering an era of effective therapy for chronic viral hepatitis. Improvements in current treatment and therapies are likely to be approved in the next several years that can double cure rates and cut the length of treatment in half and could confer increasingly greater benefits.
Until then, though, we have no time to waste. Our legislation, along with strategic investments in public health and prevention programs, will save billions of dollars and the lives of tens of thousands of people all over America. We urge our colleagues to support activities that promote early detection and education. Our legislation will sound the alarm on this silent killer.
Sen. John Kerry is a Massachusetts Democrat, and Rep. Michael M. Honda is a California Democrat.
Source
By Sen. John Kerry and Rep. Michael M. Honda
The Washington Times
6:54 p.m., Tuesday, August 10, 2010
A silent killer is loose in America. It contributes to the death of 15,000 Americans a year and threatens the health of 5.3 million more. It is more common than HIV/AIDS. It is the leading cause of liver cancer - a cancer that is on the rise and continues to be a fatal and costly disease. Yet it remains unrecognized as a serious threat to public health.
This silent killer is viral hepatitis. Most people don't even know they have it until years later, when it causes cancer or liver disease. But we can help avoid such needless tragedies with prevention and surveillance programs and by educating Americans on the pervasive nature of hepatitis B and hepatitis C.
A first step is to change the way viral hepatitis is diagnosed and treated, and that is why we have introduced legislation in the Senate and the House to provide almost $600 million over the next few years to treat this deadly epidemic. Our legislation will make our health care system more efficient. More important, it will save lives.
The bills we have introduced closely mirror the recommendations in a recent report from the Institute of Medicine (IOM), "Hepatitis and Liver Cancer," which calls for a national strategy to prevent and control hepatitis B and C.
The report concludes that the current approach is not working: Americans at risk for hepatitis or living with it do not know it, and health providers are not screening for it. That should come as no surprise because there is no federal funding of core public health services for viral hepatitis. Nor is there any federally funded chronic hepatitis B and C surveillance system.
Not surprisingly, the IOM report recommends increased information and awareness about chronic viral hepatitis among health care providers, social service providers and the public; improved surveillance for hepatitis B and hepatitis C; and better integration of viral hepatitis services.
Our call for a national strategy is not unlike IOM's. Specifically, our bills increase interagency coordination between the Centers for Disease Control and Prevention (CDC), the National Institutes of Health (NIH), the National Cancer Institute (NCI), the Health Resources and Services Administration (HRSA), the Substance Abuse and Mental Health Services Administration (SAMHSA), the Agency for Healthcare Research and Quality (AHRQ) and the Department of Veterans Affairs (VA).
It sets up programs to improve understanding of hepatitis B and C and requires the CDC to integrate them into existing immunization, prevention and control programs and support counseling. It also expands current vaccination programs and establishes a national chronic and acute hepatitis B and C surveillance program to identify incidence and prevalence in viral hepatitis and liver cancer.
Hepatitis B is 100 times more infectious than HIV and, left untreated, can cause liver disease, liver cancer and premature death decades after infection. About 2 billion people worldwide have been infected with hepatitis B, and about 170 million people are chronically infected with hepatitis C. Tragically, two-thirds of those infected, on average, are unaware of their status, which increases the chance of spreading the disease.
We cannot afford to be silent anymore. Our fellow citizens are dying daily because our nation lacks a comprehensive prevention, education and medical management program. Each year, about 15,000 people die from liver cancer or liver diseases related to hepatitis B and hepatitis C. That's more than 40 deaths every day.
Beyond the tragic and preventable loss of human life, there is the economic cost. Although the costs of education, research and treatment are not trivial, they are substantially less than the annual health care cost attributable to viral hepatitis in the United States.
Without effective prevention and vaccination methods, chronic hepatitis B and C are expected to cost our country billions of dollars in the coming years. The baby-boomer population is estimated to account for two out of every three cases of chronic hepatitis C. As these Americans age and enter into Medicare, they are likely to develop complications and require expensive medical interventions. In the next decade, the costs of hepatitis C to commercial insurance and Medicare will more than double, and within 20 years, Medicare costs will increase fivefold. Projecting further out, over the next 20 years, total medical costs for patients with hepatitis C infection could increase more than 2.5 times - from $30 billion to more than $85 billion.
Contrast the costs for early detection and intervention with the costs for treatment post-infection. The costs for hepatitis B vaccinations vary but range from $75 to $165, whereas treatment can cost up to $16,000 per year. Screening for hepatitis C is also relatively inexpensive compared to treatment, which can cost up to $25,000 per year. Untreated, these infections will develop into liver disease that can cost up to $110,000 per hospital admission.
Moreover, the United States is entering an era of effective therapy for chronic viral hepatitis. Improvements in current treatment and therapies are likely to be approved in the next several years that can double cure rates and cut the length of treatment in half and could confer increasingly greater benefits.
Until then, though, we have no time to waste. Our legislation, along with strategic investments in public health and prevention programs, will save billions of dollars and the lives of tens of thousands of people all over America. We urge our colleagues to support activities that promote early detection and education. Our legislation will sound the alarm on this silent killer.
Sen. John Kerry is a Massachusetts Democrat, and Rep. Michael M. Honda is a California Democrat.
Source
Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial - in the Lancet Aug 9 Epub -
publication pdf attached, figure 5 is very useful
"Rapid virological response was highly associated with SVR in all treatment groups. In the 28-week treatment groups, 82% (54/66) of patients in the PR4/PRB24 group and 74% (32/43) in the PRB28 group who had rapid virological response achieved SVR. In the 48-week treatment groups, 94% (62/66) of patients assigned to PR4/PRB44 and 84% (32/38) assigned to PRB48 who achieved undetectable hepatitis C virus RNA by week 4 of boceprevir achieved SVR. Achievement of undetectable hepatitis C virus RNA between weeks 4 and 12 of boceprevir therapy was also highly predictive of SVR in the 48-week treatment groups (table 3; figure 4). We noted a greater SVR in patients who cleared virus between weeks 4 and 12 of boceprevir in the PR4/PRB44 group compared with the PR4/PRB24 group (table 3).....
Thus, in the treatment of genotype 1 hepatitis C virus, nearly two-thirds of patients achieved undetectable hepatitis C virus RNA levels at week 4 of boceprevir therapy after PR4, and these individuals can be treated for 28 weeks with high SVR. Of the additional 18% (19/103) of patients who go on to achieve undetectable hepatitis C virus RNA between weeks 4 and 12 of boceprevir therapy, 79% (15/19) of patients benefit from extending therapy with peginterferon alfa-2b, ribavirin, and boceprevir to 48 weeks. Only one patient in the boceprevir groups who developed undetectable hepatitis C virus RNA after week 12 of boceprevir therapy went on to SVR."
"The lead-in (PR4) allowed us to examine the relation of peginterferon and ribavirin responsiveness at week 4 to SVR with boceprevir-containing regimens. In the PR4 28-week or 48-week groups, SVR was similar in participants with greater than 1·5 log10 reduction in hepatitis C virus RNA from baseline before the addition of boceprevir. Higher SVR was noted in participants who received PRB for 44 weeks with less than 1·5 log10 reduction from baseline at PR4 (figure 5). In patients with less than 1 log10 reduction with PR4, 55% (95% CI 32-76) SVR was noted in the PR4/PRB44 group.....
The lead-in can identify null responders to peginterferon alfa-2b and ribavirin, who seem to be at greatest risk for treatment failure with specifically targeted therapies and for development of resistance. However, in our cohort, a substantial proportion of null responders during the lead-in period went on to achieve SVR with the addition of boceprevir.....In the novel lead-in approach, we recorded increased SVR and a reduction in relapse and breakthrough, and allowed for potential determination of treatment duration on the basis of responsiveness to the PR4 lead-in. However, in the direct comparison between lead-in and non-lead-in groups, relapse reduction did not differ significantly, although the absence of a statistically conclusive result is not surprising since the sample size did not allow detection of modest differences between lead-in and non-lead-in groups. The mutations recorded in participants with viral breakthrough were consistent what those that have been previously reported with NS3 inhibitors with no new mutations noted.23-26 The clinical relevance of these mutations is unknown, and long-term follow-up is in progress."
"The SVR rate for black people in the PR48 control group was 13% (two of 16) and as high as 53% (eight of 15) in patients treated with boceprevir for 48 weeks (table 4). In patients with cirrhosis, the SVR rate was 67% (ten of 15) in the combined longer duration boceprevir groups versus 25% (two of eight) in the control group; in patients without cirrhosis, the SVR rate for the combined longer duration boceprevir groups was 71% (136/191) compared with 39% (37/96) for the control group."
"We also noted increased rates of SVR in patients who developed anaemia (haemoglobin <100 g/L) irrespective of treatment group. Epoetin alfa was used by 40% (236/595) of patients and was allowed at investigator discretion. The use of this drug in those with anaemia was also associated with an improved SVR (table 4).....
A study suggested that development of anaemia with haemoglobin less than 100 g/L is associated with increased SVR in patients receiving pegylated interferon and ribavirin; anaemia is potentially a surrogate marker of increased ribavirin concentration and the addition of epoetin alfa might allow patients to remain on therapy"
"These results are consistent with those recorded in two trials of another NS3 protease inhibitor, telaprevir, in combination with peginterferon and ribavirin, in populations that excluded those with histological cirrhosis and had fewer black people.17, 18 In one of these studies,17 undertaken in the USA, the SVR rate in the telaprevir group receiving 24 weeks of treatment with 12 weeks of telaprevir and 24 weeks of peginterferon and ribavirin was 20% higher than in the control group of 48 weeks of peginterferon and ribavirin (61% [48/79] vs 41% [31/75]); and in the telaprevir group receiving 48 weeks of treatment with 12 weeks of telaprevir added to 48 weeks of peginterferon and ribavirin, the SVR rate was 26% higher than it was in the 48-week control group (67% [53/79] vs 41% [31/75]). In the other study,18 undertaken in Europe, the SVR rate in the telaprevir group receiving 24 weeks of treatment with 12 weeks of telaprevir and 24 weeks of peginterferon and ribavirin was 23% higher than in the 48-week control group (69% [56/81] vs 46% [38/82]). Although the study designs and populations differed, in our study, SVR rates were 17-19% higher than in the control group in the 28-week boceprevir group, and 29-37% higher than control in the 48-week boceprevir groups."
Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial
The Lancet, Early Online Publication, 9 August 2010
Dr Paul Y Kwo MD a Corresponding AuthorEmail Address, Eric J Lawitz MD b, Jonathan McCone MD c, Prof Eugene R Schiff MD d, Prof John M Vierling MD e, David Pound MD f, Mitchell N Davis DO g, Joseph S Galati MD h, Stuart C Gordon MD i, Natarajan Ravendhran MD j, Prof Lorenzo Rossaro MD k, Frank H Anderson MD l, Prof Ira M Jacobson MD m, Raymond Rubin MD n, Kenneth Koury PhD o, Lisa D Pedicone PhD o, Clifford A Brass MD o, Eirum Chaudhri MD o, Janice K Albrecht PhD o
Summary
Background
Peginterferon plus ribavirin achieves sustained virological response (SVR) in fewer than half of patients with genotype 1 chronic hepatitis C virus infection treated for 48 weeks. We tested the efficacy of boceprevir, an NS3 hepatitis C virus oral protease inhibitor, when added to peginterferon alfa-2b and ribavirin.
Methods
In part 1 of this trial, undertaken in 67 sites in the USA, Canada, and Europe, 520 treatment-naive patients with genotype 1 hepatitis C virus infection were randomly assigned to receive peginterferon alfa-2b 1·5 µg/kg plus ribavirin 800-1400 mg daily for 48 weeks (PR48; n=104); peginterferon alfa-2b and ribavirin daily for 4 weeks, followed by peginterferon alfa-2b, ribavirin, and boceprevir 800 mg three times a day for 24 weeks (PR4/PRB24; n=103) or 44 weeks (PR4/PRB44; n=103); or peginterferon alfa-2b, ribavirin, and boceprevir three times a day for 28 weeks (PRB28; n=107) or 48 weeks (PRB48; n=103). In part 2, 75 patients were randomly assigned to receive either PRB48 (n=16) or low-dose ribavirin (400-1000 mg) plus peginterferon alfa-2b and boceprevir three times a day for 48 weeks (low-dose PRB48; n=59). Randomisation was by computer-generated code, and study personnel and patients were not masked to group assignment. The primary endpoint was SVR 24 weeks after treatment. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00423670.
Findings
Patients in all four boceprevir groups had higher rates of SVR than did the control group
- (58/107 [54%, 95% CI 44-64], p=0·013 for PRB28;
- 58/103 [56%, 44-66], p=0·005 for PR4/PRB24;
- 69/103 [67%, 57-76], p<0·0001 for PRB48; and
- 77/103 [75%, 65-83], p<0·0001 for PR4/PRB44;
vs 39/104 [38%, 28-48] for PR48 control).
Low-dose ribavirin was associated with a high rate of viral breakthrough (16/59 [27%]), and a rate of relapse (six of 27 [22%]) similar to control (12/51 [24%]).
Boceprevir-based groups had higher rates of anaemia (227/416 [55%] vs 35/104 [34%]) and dysgeusia (111/416 [27%] vs nine of 104 [9%]) than did the control group.
Interpretation
In patients with untreated genotype 1 chronic hepatitis C infection, the addition of the direct-acting antiviral agent boceprevir to standard treatment with peginterferon and ribavirin after a 4-week lead-in seems to have the potential to double the sustained response rate compared with that recorded with standard treatment alone.
Funding
Merck.
Introduction
Chronic hepatitis C virus affects about 170 million people worldwide. Cirrhosis induced by hepatitis C virus is the most common indication for liver transplantation and is a major contributor to the worldwide increase in the incidence of hepatocellular cancer.1, 2 Standard-of-care treatment of genotype 1 hepatitis C virus is pegylated interferon and ribavirin for 48 weeks, which results in sustained virological response (SVR) in about 40-50% of individuals.3-5 SVR rates for black patients treated with standard of care are substantially lower; in two studies undertaken almost exclusively in genotype 1 individuals, 19-28% of black people achieved SVR versus 52% of non-Hispanic white people.6, 7 Those who achieve SVR can have long-term benefits with improvement in degrees of liver fibrosis, reduction in complications of chronic liver disease, and improved quality of life.8 Studies have shown that response-guided therapy can allow tailoring of duration of treatment, with week 4 viral clearance (rapid virological response) allowing shorter duration of therapy than for those who clear virus at week 12 (complete early virological response).9-12
Up until now, treatment for this disease has consisted of therapies to stimulate the immune system and interfere in a non-specific manner with viral replication. Research has focussed on therapies that inhibit hepatitis C virus proteins that are essential for intracellular replication; these drugs are referred to as direct-acting antiviral agents.13 Boceprevir is a novel peptidomimetic NS3 protease inhibitor that forms a covalent reversible complex with the NS3 protease in vitro and has shown potent antiviral activity in the hepatitis C virus replicon system, and in patients who previously showed no response to peginterferon administered with or without ribavirin.14, 15 In a dose-ascending study in null responders,16 boceprevir, when given in combination with peginterferon alfa-2b and ribavirin, was associated with a modest incremental haemoglobin reduction, as has been recorded with other direct-acting antiviral agents in the NS3 inhibitor class.17, 18 The NS3 protease inhibitor telaprevir has also shown significantly higher rates of SVR than has standard of care in patients with genotype 1 disease when given for 12 weeks in combination with regimens of peginterferon and ribavirin lasting 12, 24, or 48 weeks.17, 18 Although rates of SVR in the telaprevir groups were higher than were those recorded with standard of care, investigators noted higher drop-out rates due to increased side-effects.
The aim of the hepatitis C virus SPRINT-1 (Serine Protease Inhibitor Therapy-1) study was to establish the safety and efficacy of boceprevir when added to peginterferon and ribavirin. We investigated treatment durations of 28 weeks versus 48 weeks, with and without a 4-week lead-in of peginterferon alfa-2b and ribavirin before the addition of boceprevir for 24 or 44 weeks, and the efficacy of low-dose ribavirin. The rationale for the 4-week lead-in was to allow pegylated interferon and ribavirin to reach steady-state concentrations before the addition of boceprevir such that backbone drug concentrations would be at an optimum and potentially reduce the likelihood for emergence of drug-resistant mutations by reducing viral levels.19-21 Part 2 of this study, which was added after enrolment in part 1 was completed, was undertaken to assess the possibility of use of a lower dose of ribavirin to reduce treatment complications, mainly anaemia. Since boceprevir and other NS3 protease inhibitors have been associated with a modest reduction in haemoglobin, weight-based low-dose (400-1000 mg per day) versus standard-dose (800-1400 mg per day) ribavirin was assessed to establish whether efficacy could be maintained while reducing anaemia. Lastly, we examined the rates of viral clearance and SVR.
Results
765 patients were screened and 595 were enrolled in 43 US, four Canadian, and 20 European Union sites. All efficacy and safety analyses were based on 595 patients who were randomly assigned and received at least one dose of medication. Table 1 shows baseline characteristics, and figures 2 and 3 show patient disposition for all groups.
Table 2 shows virological response. Irrespective of treatment duration or use of PR4 as lead-in, SVR rates in all four boceprevir groups in part 1 were significantly better than were those in the PR48 control group. In the 28-week treatment groups, the SVR was 56% (95% CI 46-66) in the PR4/PRB24 group (p=0·005 vs control) and 54% (44-64) in the PRB28 group (p=0·013 vs control). In the 48-week treatment groups, the SVR was 75% (65-83) in the PR4/PRB44 group (p<0·0001 vs control) compared with 67% (57-76) in the PRB48 group (p<0·0001 vs control). In part 2, the SVR for low-dose PRB48 was 36% (24-49).
We noted significantly lower relapse rates in the 48-week treatment groups compared with PR48 control (PRB48, p=0·0079; PR4/PRB44, p=0·0002; table 2). Although the relapse rates were higher in the 28-week than in the 48-week treatment groups, patients in the 28-week groups who had rapid hepatitis C virus RNA clearance at week 4 of boceprevir had substantially lower relapse rates than did those who did not have rapid viral clearance (p<0·0001; table 2). Low-dose PRB was associated with high relapse rates. Of note, we recorded no viral breakthrough in control groups that did not contain boceprevir (table 2). In the boceprevir groups, the lead-in groups were associated with a modestly lower rate of breakthrough than were the groups with no lead in. Combining across treatment groups, the rate of breakthrough in the boceprevir lead-in groups was 4% (nine of 206) compared with 9% (19/210) in the boceprevir groups with no lead in (p=0·057). By population sequencing, the major mutations (in >25% of samples) were V36M, T54S, and R155K, with less common (in 5% to <25%) mutations including T54A, V55A, R155T, A156S, V158I, and V170A (data not shown). Infrequent mutations (in <5% of samples) included V36A, V36L, and I170T (data not shown).
Rapid virological response was highly associated with SVR in all treatment groups. In the 28-week treatment groups, 82% (54/66) of patients in the PR4/PRB24 group and 74% (32/43) in the PRB28 group who had rapid virological response achieved SVR. In the 48-week treatment groups, 94% (62/66) of patients assigned to PR4/PRB44 and 84% (32/38) assigned to PRB48 who achieved undetectable hepatitis C virus RNA by week 4 of boceprevir achieved SVR. Achievement of undetectable hepatitis C virus RNA between weeks 4 and 12 of boceprevir therapy was also highly predictive of SVR in the 48-week treatment groups (table 3; figure 4). We noted a greater SVR in patients who cleared virus between weeks 4 and 12 of boceprevir in the PR4/PRB44 group compared with the PR4/PRB24 group (table 3).
Table 3 Rates of sustained virological relapse by time to first undetectable hepatitis C virus RNA
The lead-in (PR4) allowed us to examine the relation of peginterferon and ribavirin responsiveness at week 4 to SVR with boceprevir-containing regimens. In the PR4 28-week or 48-week groups, SVR was similar in participants with greater than 1·5 log10 reduction in hepatitis C virus RNA from baseline before the addition of boceprevir. Higher SVR was noted in participants who received PRB for 44 weeks with less than 1·5 log10 reduction from baseline at PR4 (figure 5). In patients with less than 1 log10 reduction with PR4, 55% (95% CI 32-76) SVR was noted in the PR4/PRB44 group.
A multivariate regression analysis of pooled boceprevir groups in part 1 of the study was done by investigation of baseline factors associated with SVR. These factors included low viral load (²600 000 IU/mL), non-black race, lower platelet count, and genotype 1b. In the control group of this study which received the standard of care, black people and those with cirrhosis had a lower SVR than did participants of non-black race and with no cirrhosis (table 4). The SVR rate for black people in the PR48 control group was 13% (two of 16) and as high as 53% (eight of 15) in patients treated with boceprevir for 48 weeks (table 4). In patients with cirrhosis, the SVR rate was 67% (ten of 15) in the combined longer duration boceprevir groups versus 25% (two of eight) in the control group; in patients without cirrhosis, the SVR rate for the combined longer duration boceprevir groups was 71% (136/191) compared with 39% (37/96) for the control group.
We also noted increased rates of SVR in patients who developed anaemia (haemoglobin <100 g/L) irrespective of treatment group. Epoetin alfa was used by 40% (236/595) of patients and was allowed at investigator discretion. The use of this drug in those with anaemia was also associated with an improved SVR (table 4).
The most common adverse events in the boceprevir groups, as reported by investigators, were fatigue, anaemia, nausea, and headache-a side-effect profile generally similar to that recorded in patients receiving PR48 control. The rate of dysgeusia and anaemia was higher in the boceprevir groups than in other groups (table 5). In the boceprevir groups, we detected nadir haemoglobin concentrations of 85-100 g/L in those who developed anaemia; and haemoglobin concentrations less than 85 g/L were rare (table 6). Dose modifications of ribavirin were similar in boceprevir groups compared with the PR48 control group, and boceprevir dose modifications were rare (table 7). We recorded an overall higher discontinuation rate in the boceprevir groups than in the control group (table 7). Treatment discontinuations attributable to adverse events ranged from 9% to 19% in the groups receiving boceprevir therapy compared with 8% for the PR48 group, with two patients discontinuing treatment because of anaemia in the boceprevir groups (table 7). The rate of adverse events categorised as skin and subcutaneous tissue disorders was similar in boceprevir-containing regimens (159/416, 38%) and the control group (38/104, 37%).
Discussion
The results of this phase 2 trial have shown that an optimum dose of boceprevir (800 mg three times a day), when added to the standard of care for treatment of chronic genotype 1 hepatitis C virus, significantly increased SVR in both 28-week and 48-week regimens compared with the control of peginterferon alfa-2b and ribavirin. Responses in the 48-week boceprevir groups were substantially higher than were those in the 28-week groups, with a near doubling of SVR in the PR4/PRB44 group. The use of low-dose ribavirin in combination with peginterferon and boceprevir, while reducing haematological toxic effects, did not improve SVR rates compared with control.
These results are consistent with those recorded in two trials of another NS3 protease inhibitor, telaprevir, in combination with peginterferon and ribavirin, in populations that excluded those with histological cirrhosis and had fewer black people.17, 18 In one of these studies,17 undertaken in the USA, the SVR rate in the telaprevir group receiving 24 weeks of treatment with 12 weeks of telaprevir and 24 weeks of peginterferon and ribavirin was 20% higher than in the control group of 48 weeks of peginterferon and ribavirin (61% [48/79] vs 41% [31/75]); and in the telaprevir group receiving 48 weeks of treatment with 12 weeks of telaprevir added to 48 weeks of peginterferon and ribavirin, the SVR rate was 26% higher than it was in the 48-week control group (67% [53/79] vs 41% [31/75]). In the other study,18 undertaken in Europe, the SVR rate in the telaprevir group receiving 24 weeks of treatment with 12 weeks of telaprevir and 24 weeks of peginterferon and ribavirin was 23% higher than in the 48-week control group (69% [56/81] vs 46% [38/82]). Although the study designs and populations differed, in our study, SVR rates were 17-19% higher than in the control group in the 28-week boceprevir group, and 29-37% higher than control in the 48-week boceprevir groups.
In black participants and in those with cirrhosis, the addition of boceprevir to standard of care improved SVR. These preliminary results in a fairly small number of patients suggest that the addition of boceprevir to peginterferon alfa-2b and ribavirin will improve SVR in these difficult-to-treat populations. This study assessed the use of a PR4 lead-in before the addition of boceprevir, as well as the effect of starting all three drugs concomitantly, and compared these groups with PR48 control. In the novel lead-in approach, we recorded increased SVR and a reduction in relapse and breakthrough, and allowed for potential determination of treatment duration on the basis of responsiveness to the PR4 lead-in. However, in the direct comparison between lead-in and non-lead-in groups, relapse reduction did not differ significantly, although the absence of a statistically conclusive result is not surprising since the sample size did not allow detection of modest differences between lead-in and non-lead-in groups. The mutations recorded in participants with viral breakthrough were consistent what those that have been previously reported with NS3 inhibitors with no new mutations noted.23-26 The clinical relevance of these mutations is unknown, and long-term follow-up is in progress.
The viral response during the lead-in could help to predict best possible treatment duration. Patients achieving less than 1·5 log10 reduction in viral level after PR4 benefit most from a treatment duration of 48 weeks, whereas those with greater than 1·5 log10 reduction show similar SVR irrespective of treatment duration of 28 weeks or 48 weeks. The lead-in can identify null responders to peginterferon alfa-2b and ribavirin, who seem to be at greatest risk for treatment failure with specifically targeted therapies and for development of resistance. However, in our cohort, a substantial proportion of null responders during the lead-in period went on to achieve SVR with the addition of boceprevir.16, 27
In all groups, rapid virological response was highly predictive of SVR. We also recorded high rates of rapid virological response in the 48-week treatment groups. Participants who cleared virus between weeks 4 and 12 of boceprevir therapy were more likely to go on to SVR if they received 48 weeks of treatment rather than 28 weeks. Thus, in the treatment of genotype 1 hepatitis C virus, nearly two-thirds of patients achieved undetectable hepatitis C virus RNA levels at week 4 of boceprevir therapy after PR4, and these individuals can be treated for 28 weeks with high SVR. Of the additional 18% (19/103) of patients who go on to achieve undetectable hepatitis C virus RNA between weeks 4 and 12 of boceprevir therapy, 79% (15/19) of patients benefit from extending therapy with peginterferon alfa-2b, ribavirin, and boceprevir to 48 weeks. Only one patient in the boceprevir groups who developed undetectable hepatitis C virus RNA after week 12 of boceprevir therapy went on to SVR.
We noted no new adverse events or treatment-limiting toxic effects associated with boceprevir-containing regimens in this trial compared with those recorded in patients receiving peginterferon and ribavirin. No increases in skin or subcutaneous adverse events were noted in the boceprevir-containing groups compared with the control groups. Higher rates of both anaemia and dysgeusia were noted in the boceprevir-containing regimens than in the control group, although stopping treatment for anaemia was rare. Haemoglobin reductions in the PRB48 low-dose group were less than those in the control group and in any of the full-dose PRB groups in part 1, and similar to the haemoglobin reduction in the PR48 group of part 1 of the study. In this study, use of epoetin alfa was allowed at the investigator's discretion and was associated with improved SVR. A study suggested that development of anaemia with haemoglobin less than 100 g/L is associated with increased SVR in patients receiving pegylated interferon and ribavirin; anaemia is potentially a surrogate marker of increased ribavirin concentration and the addition of epoetin alfa might allow patients to remain on therapy.28 In our study, the development of anaemia and the use of epoetin alfa were associated with improved SVR in the boceprevir-containing regimens. However, since there was no randomisation for use of epoetin alfa in this study, the contributions of anaemia and epoetin alfa use to improved SVR with boceprevir remains to be established. The role of epoetin alfa as an adjuvant in patients receiving pegylated interferon and ribavirin in addition to therapy with direct-acting antiviral agents deserves further study. We recorded a higher drop-out rate in the boceprevir-containing groups than in the control group, as has been noted when other direct-acting antiviral agents are added to peginterferon alfa-2b and ribavirin.17 This findings suggests that treating physicians might need experience with these agents to ensure patient adherence and manage side-effects, as was noted with the introduction of ribavirin to interferon therapy for hepatitis C virus infection.17, 18
There are potential limitations of this study which deserve mention. This was an open-label study with regard to the administration of boceprevir because of the complex study design with comparisons of lead-in and non-lead-in groups, and differing treatment durations. However, all assays were done by an independent commercial laboratory that did not have access to participant treatment assignments. The primary and other key study endpoints were based on hepatitis C virus RNA level-an outcome that is not subject to bias. Another possible limitation concerns the stratification of patients as with or without cirrhosis. We required a liver biopsy sample to be taken within 5 years of enrolment into the study. A patient who tested negative for cirrhosis 5 years before the beginning of the study could have developed cirrhosis in the intervening years. Thus patients with cirrhosis could have been mischaracterised as being non-cirrhotic, biasing the results in favour of the population with this disease. Therefore, the promising results obtained in patients with cirrhosis who received boceprevir will need confirmation in larger trials that are in progress.
In conclusion, boceprevir, in combination with pegylated interferon and ribavirin, achieved high SVR rates with 28 weeks of therapy in most patients and is safe and effective for use up to 48 weeks in the few patients who benefit from longer duration of therapy. We also recorded increased response rates in difficult-to-treat groups, including black participants and those with cirrhosis. The use of PR4 lead-in before the addition of boceprevir improves SVR over a 48-week duration, and reduces viral breakthrough and relapse. A large confirmatory trial is in progress and will define the best treatment regimen for the use of boceprevir in the treatment of genotype 1 chronic hepatitis C virus infection.
Source
"Rapid virological response was highly associated with SVR in all treatment groups. In the 28-week treatment groups, 82% (54/66) of patients in the PR4/PRB24 group and 74% (32/43) in the PRB28 group who had rapid virological response achieved SVR. In the 48-week treatment groups, 94% (62/66) of patients assigned to PR4/PRB44 and 84% (32/38) assigned to PRB48 who achieved undetectable hepatitis C virus RNA by week 4 of boceprevir achieved SVR. Achievement of undetectable hepatitis C virus RNA between weeks 4 and 12 of boceprevir therapy was also highly predictive of SVR in the 48-week treatment groups (table 3; figure 4). We noted a greater SVR in patients who cleared virus between weeks 4 and 12 of boceprevir in the PR4/PRB44 group compared with the PR4/PRB24 group (table 3).....
Thus, in the treatment of genotype 1 hepatitis C virus, nearly two-thirds of patients achieved undetectable hepatitis C virus RNA levels at week 4 of boceprevir therapy after PR4, and these individuals can be treated for 28 weeks with high SVR. Of the additional 18% (19/103) of patients who go on to achieve undetectable hepatitis C virus RNA between weeks 4 and 12 of boceprevir therapy, 79% (15/19) of patients benefit from extending therapy with peginterferon alfa-2b, ribavirin, and boceprevir to 48 weeks. Only one patient in the boceprevir groups who developed undetectable hepatitis C virus RNA after week 12 of boceprevir therapy went on to SVR."
"The lead-in (PR4) allowed us to examine the relation of peginterferon and ribavirin responsiveness at week 4 to SVR with boceprevir-containing regimens. In the PR4 28-week or 48-week groups, SVR was similar in participants with greater than 1·5 log10 reduction in hepatitis C virus RNA from baseline before the addition of boceprevir. Higher SVR was noted in participants who received PRB for 44 weeks with less than 1·5 log10 reduction from baseline at PR4 (figure 5). In patients with less than 1 log10 reduction with PR4, 55% (95% CI 32-76) SVR was noted in the PR4/PRB44 group.....
The lead-in can identify null responders to peginterferon alfa-2b and ribavirin, who seem to be at greatest risk for treatment failure with specifically targeted therapies and for development of resistance. However, in our cohort, a substantial proportion of null responders during the lead-in period went on to achieve SVR with the addition of boceprevir.....In the novel lead-in approach, we recorded increased SVR and a reduction in relapse and breakthrough, and allowed for potential determination of treatment duration on the basis of responsiveness to the PR4 lead-in. However, in the direct comparison between lead-in and non-lead-in groups, relapse reduction did not differ significantly, although the absence of a statistically conclusive result is not surprising since the sample size did not allow detection of modest differences between lead-in and non-lead-in groups. The mutations recorded in participants with viral breakthrough were consistent what those that have been previously reported with NS3 inhibitors with no new mutations noted.23-26 The clinical relevance of these mutations is unknown, and long-term follow-up is in progress."
"The SVR rate for black people in the PR48 control group was 13% (two of 16) and as high as 53% (eight of 15) in patients treated with boceprevir for 48 weeks (table 4). In patients with cirrhosis, the SVR rate was 67% (ten of 15) in the combined longer duration boceprevir groups versus 25% (two of eight) in the control group; in patients without cirrhosis, the SVR rate for the combined longer duration boceprevir groups was 71% (136/191) compared with 39% (37/96) for the control group."
"We also noted increased rates of SVR in patients who developed anaemia (haemoglobin <100 g/L) irrespective of treatment group. Epoetin alfa was used by 40% (236/595) of patients and was allowed at investigator discretion. The use of this drug in those with anaemia was also associated with an improved SVR (table 4).....
A study suggested that development of anaemia with haemoglobin less than 100 g/L is associated with increased SVR in patients receiving pegylated interferon and ribavirin; anaemia is potentially a surrogate marker of increased ribavirin concentration and the addition of epoetin alfa might allow patients to remain on therapy"
"These results are consistent with those recorded in two trials of another NS3 protease inhibitor, telaprevir, in combination with peginterferon and ribavirin, in populations that excluded those with histological cirrhosis and had fewer black people.17, 18 In one of these studies,17 undertaken in the USA, the SVR rate in the telaprevir group receiving 24 weeks of treatment with 12 weeks of telaprevir and 24 weeks of peginterferon and ribavirin was 20% higher than in the control group of 48 weeks of peginterferon and ribavirin (61% [48/79] vs 41% [31/75]); and in the telaprevir group receiving 48 weeks of treatment with 12 weeks of telaprevir added to 48 weeks of peginterferon and ribavirin, the SVR rate was 26% higher than it was in the 48-week control group (67% [53/79] vs 41% [31/75]). In the other study,18 undertaken in Europe, the SVR rate in the telaprevir group receiving 24 weeks of treatment with 12 weeks of telaprevir and 24 weeks of peginterferon and ribavirin was 23% higher than in the 48-week control group (69% [56/81] vs 46% [38/82]). Although the study designs and populations differed, in our study, SVR rates were 17-19% higher than in the control group in the 28-week boceprevir group, and 29-37% higher than control in the 48-week boceprevir groups."
Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial
The Lancet, Early Online Publication, 9 August 2010
Dr Paul Y Kwo MD a Corresponding AuthorEmail Address, Eric J Lawitz MD b, Jonathan McCone MD c, Prof Eugene R Schiff MD d, Prof John M Vierling MD e, David Pound MD f, Mitchell N Davis DO g, Joseph S Galati MD h, Stuart C Gordon MD i, Natarajan Ravendhran MD j, Prof Lorenzo Rossaro MD k, Frank H Anderson MD l, Prof Ira M Jacobson MD m, Raymond Rubin MD n, Kenneth Koury PhD o, Lisa D Pedicone PhD o, Clifford A Brass MD o, Eirum Chaudhri MD o, Janice K Albrecht PhD o
Summary
Background
Peginterferon plus ribavirin achieves sustained virological response (SVR) in fewer than half of patients with genotype 1 chronic hepatitis C virus infection treated for 48 weeks. We tested the efficacy of boceprevir, an NS3 hepatitis C virus oral protease inhibitor, when added to peginterferon alfa-2b and ribavirin.
Methods
In part 1 of this trial, undertaken in 67 sites in the USA, Canada, and Europe, 520 treatment-naive patients with genotype 1 hepatitis C virus infection were randomly assigned to receive peginterferon alfa-2b 1·5 µg/kg plus ribavirin 800-1400 mg daily for 48 weeks (PR48; n=104); peginterferon alfa-2b and ribavirin daily for 4 weeks, followed by peginterferon alfa-2b, ribavirin, and boceprevir 800 mg three times a day for 24 weeks (PR4/PRB24; n=103) or 44 weeks (PR4/PRB44; n=103); or peginterferon alfa-2b, ribavirin, and boceprevir three times a day for 28 weeks (PRB28; n=107) or 48 weeks (PRB48; n=103). In part 2, 75 patients were randomly assigned to receive either PRB48 (n=16) or low-dose ribavirin (400-1000 mg) plus peginterferon alfa-2b and boceprevir three times a day for 48 weeks (low-dose PRB48; n=59). Randomisation was by computer-generated code, and study personnel and patients were not masked to group assignment. The primary endpoint was SVR 24 weeks after treatment. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00423670.
Findings
Patients in all four boceprevir groups had higher rates of SVR than did the control group
- (58/107 [54%, 95% CI 44-64], p=0·013 for PRB28;
- 58/103 [56%, 44-66], p=0·005 for PR4/PRB24;
- 69/103 [67%, 57-76], p<0·0001 for PRB48; and
- 77/103 [75%, 65-83], p<0·0001 for PR4/PRB44;
vs 39/104 [38%, 28-48] for PR48 control).
Low-dose ribavirin was associated with a high rate of viral breakthrough (16/59 [27%]), and a rate of relapse (six of 27 [22%]) similar to control (12/51 [24%]).
Boceprevir-based groups had higher rates of anaemia (227/416 [55%] vs 35/104 [34%]) and dysgeusia (111/416 [27%] vs nine of 104 [9%]) than did the control group.
Interpretation
In patients with untreated genotype 1 chronic hepatitis C infection, the addition of the direct-acting antiviral agent boceprevir to standard treatment with peginterferon and ribavirin after a 4-week lead-in seems to have the potential to double the sustained response rate compared with that recorded with standard treatment alone.
Funding
Merck.
Introduction
Chronic hepatitis C virus affects about 170 million people worldwide. Cirrhosis induced by hepatitis C virus is the most common indication for liver transplantation and is a major contributor to the worldwide increase in the incidence of hepatocellular cancer.1, 2 Standard-of-care treatment of genotype 1 hepatitis C virus is pegylated interferon and ribavirin for 48 weeks, which results in sustained virological response (SVR) in about 40-50% of individuals.3-5 SVR rates for black patients treated with standard of care are substantially lower; in two studies undertaken almost exclusively in genotype 1 individuals, 19-28% of black people achieved SVR versus 52% of non-Hispanic white people.6, 7 Those who achieve SVR can have long-term benefits with improvement in degrees of liver fibrosis, reduction in complications of chronic liver disease, and improved quality of life.8 Studies have shown that response-guided therapy can allow tailoring of duration of treatment, with week 4 viral clearance (rapid virological response) allowing shorter duration of therapy than for those who clear virus at week 12 (complete early virological response).9-12
Up until now, treatment for this disease has consisted of therapies to stimulate the immune system and interfere in a non-specific manner with viral replication. Research has focussed on therapies that inhibit hepatitis C virus proteins that are essential for intracellular replication; these drugs are referred to as direct-acting antiviral agents.13 Boceprevir is a novel peptidomimetic NS3 protease inhibitor that forms a covalent reversible complex with the NS3 protease in vitro and has shown potent antiviral activity in the hepatitis C virus replicon system, and in patients who previously showed no response to peginterferon administered with or without ribavirin.14, 15 In a dose-ascending study in null responders,16 boceprevir, when given in combination with peginterferon alfa-2b and ribavirin, was associated with a modest incremental haemoglobin reduction, as has been recorded with other direct-acting antiviral agents in the NS3 inhibitor class.17, 18 The NS3 protease inhibitor telaprevir has also shown significantly higher rates of SVR than has standard of care in patients with genotype 1 disease when given for 12 weeks in combination with regimens of peginterferon and ribavirin lasting 12, 24, or 48 weeks.17, 18 Although rates of SVR in the telaprevir groups were higher than were those recorded with standard of care, investigators noted higher drop-out rates due to increased side-effects.
The aim of the hepatitis C virus SPRINT-1 (Serine Protease Inhibitor Therapy-1) study was to establish the safety and efficacy of boceprevir when added to peginterferon and ribavirin. We investigated treatment durations of 28 weeks versus 48 weeks, with and without a 4-week lead-in of peginterferon alfa-2b and ribavirin before the addition of boceprevir for 24 or 44 weeks, and the efficacy of low-dose ribavirin. The rationale for the 4-week lead-in was to allow pegylated interferon and ribavirin to reach steady-state concentrations before the addition of boceprevir such that backbone drug concentrations would be at an optimum and potentially reduce the likelihood for emergence of drug-resistant mutations by reducing viral levels.19-21 Part 2 of this study, which was added after enrolment in part 1 was completed, was undertaken to assess the possibility of use of a lower dose of ribavirin to reduce treatment complications, mainly anaemia. Since boceprevir and other NS3 protease inhibitors have been associated with a modest reduction in haemoglobin, weight-based low-dose (400-1000 mg per day) versus standard-dose (800-1400 mg per day) ribavirin was assessed to establish whether efficacy could be maintained while reducing anaemia. Lastly, we examined the rates of viral clearance and SVR.
Results
765 patients were screened and 595 were enrolled in 43 US, four Canadian, and 20 European Union sites. All efficacy and safety analyses were based on 595 patients who were randomly assigned and received at least one dose of medication. Table 1 shows baseline characteristics, and figures 2 and 3 show patient disposition for all groups.
Table 2 shows virological response. Irrespective of treatment duration or use of PR4 as lead-in, SVR rates in all four boceprevir groups in part 1 were significantly better than were those in the PR48 control group. In the 28-week treatment groups, the SVR was 56% (95% CI 46-66) in the PR4/PRB24 group (p=0·005 vs control) and 54% (44-64) in the PRB28 group (p=0·013 vs control). In the 48-week treatment groups, the SVR was 75% (65-83) in the PR4/PRB44 group (p<0·0001 vs control) compared with 67% (57-76) in the PRB48 group (p<0·0001 vs control). In part 2, the SVR for low-dose PRB48 was 36% (24-49).
We noted significantly lower relapse rates in the 48-week treatment groups compared with PR48 control (PRB48, p=0·0079; PR4/PRB44, p=0·0002; table 2). Although the relapse rates were higher in the 28-week than in the 48-week treatment groups, patients in the 28-week groups who had rapid hepatitis C virus RNA clearance at week 4 of boceprevir had substantially lower relapse rates than did those who did not have rapid viral clearance (p<0·0001; table 2). Low-dose PRB was associated with high relapse rates. Of note, we recorded no viral breakthrough in control groups that did not contain boceprevir (table 2). In the boceprevir groups, the lead-in groups were associated with a modestly lower rate of breakthrough than were the groups with no lead in. Combining across treatment groups, the rate of breakthrough in the boceprevir lead-in groups was 4% (nine of 206) compared with 9% (19/210) in the boceprevir groups with no lead in (p=0·057). By population sequencing, the major mutations (in >25% of samples) were V36M, T54S, and R155K, with less common (in 5% to <25%) mutations including T54A, V55A, R155T, A156S, V158I, and V170A (data not shown). Infrequent mutations (in <5% of samples) included V36A, V36L, and I170T (data not shown).
Rapid virological response was highly associated with SVR in all treatment groups. In the 28-week treatment groups, 82% (54/66) of patients in the PR4/PRB24 group and 74% (32/43) in the PRB28 group who had rapid virological response achieved SVR. In the 48-week treatment groups, 94% (62/66) of patients assigned to PR4/PRB44 and 84% (32/38) assigned to PRB48 who achieved undetectable hepatitis C virus RNA by week 4 of boceprevir achieved SVR. Achievement of undetectable hepatitis C virus RNA between weeks 4 and 12 of boceprevir therapy was also highly predictive of SVR in the 48-week treatment groups (table 3; figure 4). We noted a greater SVR in patients who cleared virus between weeks 4 and 12 of boceprevir in the PR4/PRB44 group compared with the PR4/PRB24 group (table 3).
Table 3 Rates of sustained virological relapse by time to first undetectable hepatitis C virus RNA
The lead-in (PR4) allowed us to examine the relation of peginterferon and ribavirin responsiveness at week 4 to SVR with boceprevir-containing regimens. In the PR4 28-week or 48-week groups, SVR was similar in participants with greater than 1·5 log10 reduction in hepatitis C virus RNA from baseline before the addition of boceprevir. Higher SVR was noted in participants who received PRB for 44 weeks with less than 1·5 log10 reduction from baseline at PR4 (figure 5). In patients with less than 1 log10 reduction with PR4, 55% (95% CI 32-76) SVR was noted in the PR4/PRB44 group.
A multivariate regression analysis of pooled boceprevir groups in part 1 of the study was done by investigation of baseline factors associated with SVR. These factors included low viral load (²600 000 IU/mL), non-black race, lower platelet count, and genotype 1b. In the control group of this study which received the standard of care, black people and those with cirrhosis had a lower SVR than did participants of non-black race and with no cirrhosis (table 4). The SVR rate for black people in the PR48 control group was 13% (two of 16) and as high as 53% (eight of 15) in patients treated with boceprevir for 48 weeks (table 4). In patients with cirrhosis, the SVR rate was 67% (ten of 15) in the combined longer duration boceprevir groups versus 25% (two of eight) in the control group; in patients without cirrhosis, the SVR rate for the combined longer duration boceprevir groups was 71% (136/191) compared with 39% (37/96) for the control group.
We also noted increased rates of SVR in patients who developed anaemia (haemoglobin <100 g/L) irrespective of treatment group. Epoetin alfa was used by 40% (236/595) of patients and was allowed at investigator discretion. The use of this drug in those with anaemia was also associated with an improved SVR (table 4).
The most common adverse events in the boceprevir groups, as reported by investigators, were fatigue, anaemia, nausea, and headache-a side-effect profile generally similar to that recorded in patients receiving PR48 control. The rate of dysgeusia and anaemia was higher in the boceprevir groups than in other groups (table 5). In the boceprevir groups, we detected nadir haemoglobin concentrations of 85-100 g/L in those who developed anaemia; and haemoglobin concentrations less than 85 g/L were rare (table 6). Dose modifications of ribavirin were similar in boceprevir groups compared with the PR48 control group, and boceprevir dose modifications were rare (table 7). We recorded an overall higher discontinuation rate in the boceprevir groups than in the control group (table 7). Treatment discontinuations attributable to adverse events ranged from 9% to 19% in the groups receiving boceprevir therapy compared with 8% for the PR48 group, with two patients discontinuing treatment because of anaemia in the boceprevir groups (table 7). The rate of adverse events categorised as skin and subcutaneous tissue disorders was similar in boceprevir-containing regimens (159/416, 38%) and the control group (38/104, 37%).
Discussion
The results of this phase 2 trial have shown that an optimum dose of boceprevir (800 mg three times a day), when added to the standard of care for treatment of chronic genotype 1 hepatitis C virus, significantly increased SVR in both 28-week and 48-week regimens compared with the control of peginterferon alfa-2b and ribavirin. Responses in the 48-week boceprevir groups were substantially higher than were those in the 28-week groups, with a near doubling of SVR in the PR4/PRB44 group. The use of low-dose ribavirin in combination with peginterferon and boceprevir, while reducing haematological toxic effects, did not improve SVR rates compared with control.
These results are consistent with those recorded in two trials of another NS3 protease inhibitor, telaprevir, in combination with peginterferon and ribavirin, in populations that excluded those with histological cirrhosis and had fewer black people.17, 18 In one of these studies,17 undertaken in the USA, the SVR rate in the telaprevir group receiving 24 weeks of treatment with 12 weeks of telaprevir and 24 weeks of peginterferon and ribavirin was 20% higher than in the control group of 48 weeks of peginterferon and ribavirin (61% [48/79] vs 41% [31/75]); and in the telaprevir group receiving 48 weeks of treatment with 12 weeks of telaprevir added to 48 weeks of peginterferon and ribavirin, the SVR rate was 26% higher than it was in the 48-week control group (67% [53/79] vs 41% [31/75]). In the other study,18 undertaken in Europe, the SVR rate in the telaprevir group receiving 24 weeks of treatment with 12 weeks of telaprevir and 24 weeks of peginterferon and ribavirin was 23% higher than in the 48-week control group (69% [56/81] vs 46% [38/82]). Although the study designs and populations differed, in our study, SVR rates were 17-19% higher than in the control group in the 28-week boceprevir group, and 29-37% higher than control in the 48-week boceprevir groups.
In black participants and in those with cirrhosis, the addition of boceprevir to standard of care improved SVR. These preliminary results in a fairly small number of patients suggest that the addition of boceprevir to peginterferon alfa-2b and ribavirin will improve SVR in these difficult-to-treat populations. This study assessed the use of a PR4 lead-in before the addition of boceprevir, as well as the effect of starting all three drugs concomitantly, and compared these groups with PR48 control. In the novel lead-in approach, we recorded increased SVR and a reduction in relapse and breakthrough, and allowed for potential determination of treatment duration on the basis of responsiveness to the PR4 lead-in. However, in the direct comparison between lead-in and non-lead-in groups, relapse reduction did not differ significantly, although the absence of a statistically conclusive result is not surprising since the sample size did not allow detection of modest differences between lead-in and non-lead-in groups. The mutations recorded in participants with viral breakthrough were consistent what those that have been previously reported with NS3 inhibitors with no new mutations noted.23-26 The clinical relevance of these mutations is unknown, and long-term follow-up is in progress.
The viral response during the lead-in could help to predict best possible treatment duration. Patients achieving less than 1·5 log10 reduction in viral level after PR4 benefit most from a treatment duration of 48 weeks, whereas those with greater than 1·5 log10 reduction show similar SVR irrespective of treatment duration of 28 weeks or 48 weeks. The lead-in can identify null responders to peginterferon alfa-2b and ribavirin, who seem to be at greatest risk for treatment failure with specifically targeted therapies and for development of resistance. However, in our cohort, a substantial proportion of null responders during the lead-in period went on to achieve SVR with the addition of boceprevir.16, 27
In all groups, rapid virological response was highly predictive of SVR. We also recorded high rates of rapid virological response in the 48-week treatment groups. Participants who cleared virus between weeks 4 and 12 of boceprevir therapy were more likely to go on to SVR if they received 48 weeks of treatment rather than 28 weeks. Thus, in the treatment of genotype 1 hepatitis C virus, nearly two-thirds of patients achieved undetectable hepatitis C virus RNA levels at week 4 of boceprevir therapy after PR4, and these individuals can be treated for 28 weeks with high SVR. Of the additional 18% (19/103) of patients who go on to achieve undetectable hepatitis C virus RNA between weeks 4 and 12 of boceprevir therapy, 79% (15/19) of patients benefit from extending therapy with peginterferon alfa-2b, ribavirin, and boceprevir to 48 weeks. Only one patient in the boceprevir groups who developed undetectable hepatitis C virus RNA after week 12 of boceprevir therapy went on to SVR.
We noted no new adverse events or treatment-limiting toxic effects associated with boceprevir-containing regimens in this trial compared with those recorded in patients receiving peginterferon and ribavirin. No increases in skin or subcutaneous adverse events were noted in the boceprevir-containing groups compared with the control groups. Higher rates of both anaemia and dysgeusia were noted in the boceprevir-containing regimens than in the control group, although stopping treatment for anaemia was rare. Haemoglobin reductions in the PRB48 low-dose group were less than those in the control group and in any of the full-dose PRB groups in part 1, and similar to the haemoglobin reduction in the PR48 group of part 1 of the study. In this study, use of epoetin alfa was allowed at the investigator's discretion and was associated with improved SVR. A study suggested that development of anaemia with haemoglobin less than 100 g/L is associated with increased SVR in patients receiving pegylated interferon and ribavirin; anaemia is potentially a surrogate marker of increased ribavirin concentration and the addition of epoetin alfa might allow patients to remain on therapy.28 In our study, the development of anaemia and the use of epoetin alfa were associated with improved SVR in the boceprevir-containing regimens. However, since there was no randomisation for use of epoetin alfa in this study, the contributions of anaemia and epoetin alfa use to improved SVR with boceprevir remains to be established. The role of epoetin alfa as an adjuvant in patients receiving pegylated interferon and ribavirin in addition to therapy with direct-acting antiviral agents deserves further study. We recorded a higher drop-out rate in the boceprevir-containing groups than in the control group, as has been noted when other direct-acting antiviral agents are added to peginterferon alfa-2b and ribavirin.17 This findings suggests that treating physicians might need experience with these agents to ensure patient adherence and manage side-effects, as was noted with the introduction of ribavirin to interferon therapy for hepatitis C virus infection.17, 18
There are potential limitations of this study which deserve mention. This was an open-label study with regard to the administration of boceprevir because of the complex study design with comparisons of lead-in and non-lead-in groups, and differing treatment durations. However, all assays were done by an independent commercial laboratory that did not have access to participant treatment assignments. The primary and other key study endpoints were based on hepatitis C virus RNA level-an outcome that is not subject to bias. Another possible limitation concerns the stratification of patients as with or without cirrhosis. We required a liver biopsy sample to be taken within 5 years of enrolment into the study. A patient who tested negative for cirrhosis 5 years before the beginning of the study could have developed cirrhosis in the intervening years. Thus patients with cirrhosis could have been mischaracterised as being non-cirrhotic, biasing the results in favour of the population with this disease. Therefore, the promising results obtained in patients with cirrhosis who received boceprevir will need confirmation in larger trials that are in progress.
In conclusion, boceprevir, in combination with pegylated interferon and ribavirin, achieved high SVR rates with 28 weeks of therapy in most patients and is safe and effective for use up to 48 weeks in the few patients who benefit from longer duration of therapy. We also recorded increased response rates in difficult-to-treat groups, including black participants and those with cirrhosis. The use of PR4 lead-in before the addition of boceprevir improves SVR over a 48-week duration, and reduces viral breakthrough and relapse. A large confirmatory trial is in progress and will define the best treatment regimen for the use of boceprevir in the treatment of genotype 1 chronic hepatitis C virus infection.
Source
Phase 1b study of pegylated interferon lambda 1 with or without ribavirin in patients with chronic genotype 1 hepatitis C virus infection - publication pdf attached
publication pdf attached, figure 5 is very useful
Andrew J. Muir 1,2,*,, Mitchell L. Shiffman 3, Atif Zaman 4, Boris Yoffe 5, Andrew de la Torre 6, Steven Flamm 7, Stuart C. Gordon 8, Paul Marotta 9, John M. Vierling 10, Juan Carlos Lopez-Talavera 11, Kelly Byrnes-Blake 12, David Fontana 12, Jeremy Freeman 12, Todd Gray 12, Diana Hausman 12, Naomi N. Hunder 12, Eric Lawitz 13
Hepatology Article first published online: 14 MAY 2010
"The findings from this study offer evidence that PEG-IFN-λ, given QW for 4 weeks, exhibits potent antiviral effects against HCV with the potential for an improved tolerability profile with respect to that traditionally observed for PEG-IFN-α. These results are being tested in larger randomized controlled trials enrolling treatment-naive patients."
ABSTRACT
Interferon lambda 1 (IFN-λ1) is a type III IFN that produces intracellular responses similar to those of IFN-α but in fewer cell types because of differences in the receptor distribution pattern, and this could potentially result in an improved safety profile. This was an open-label three-part study of patients with chronic hepatitis C virus (HCV) genotype 1 infection. Part 1 evaluated single-agent pegylated interferon lambda (PEG-IFN-λ) at 1.5 or 3.0 µg/kg administered every 2 weeks or weekly for 4 weeks in patients who had relapsed after previous IFN-α-based treatment. Part 2 evaluated weekly doses of PEG-IFN-λ ranging from 0.5 to 2.25 µg/kg in combination with ribavirin (RBV) for 4 weeks in treatment-relapse patients. Part 3 evaluated weekly PEG-IFN-λ at 1.5 µg/kg in combination with RBV for 4 weeks in treatment-naive patients. Fifty-six patients were enrolled: 24 patients in part 1, 25 patients in part 2, and 7 patients in part 3. Antiviral activity was observed at all PEG-IFN-λ dose levels (from 0.5 to 3.0 µg/kg). Two of seven treatment-naive patients (29%) achieved rapid virological response. Treatment was well tolerated with minimal flu-like symptoms and no significant hematologic changes other than RBV-associated decreases in hemoglobin. The most common adverse events were fatigue (29%), nausea (12%), and myalgia (11%). Six patients experienced increases in aminotransferases that met protocol-defined criteria for dose-limiting toxicity (DLT) or temporarily holding therapy with PEG-IFN-λ. Most DLT occurred in patients with high PEG-IFN-λ exposure. Conclusion: Weekly PEG-IFN-λ with or without daily RBV for 4 weeks is well tolerated with minimal adverse events and hematologic effects and is associated with clear antiviral activity across a broad range of doses in patients with chronic HCV. (HEPATOLOGY 2010;)
The World Health Organization estimates that 180 million people worldwide (3% of the world population) are infected with hepatitis C virus (HCV), and 130 million of these are chronic HCV carriers.1 Chronic HCV infection is responsible for 50% to 76% of all liver cancer cases, two-thirds of all liver transplants in the developed world, and considerable morbidity and mortality. Identifying effective treatments for chronic HCV infection is therefore a global health priority.1
Consensus guidelines for the treatment of hepatitis C recommend a regimen of pegylated interferon alfa (PEG-IFN-α) and ribavirin (RBV).2 However, this treatment regimen results in sustained virological response (SVR) rates of only 40% in patients with genotype 1 HCV, and associated adverse events include flu-like symptoms, fatigue, depression, anxiety, and bone marrow suppression, which results in anemia, neutropenia, and thrombocytopenia.2-6 PEG-IFN-α is contraindicated in patients with major uncontrolled depressive illness and should be used with caution in patients with any psychiatric illness.2, 5-7 Other contraindications for the use of interferon alpha (IFN-α)-based regimens include hepatic decompensation, autoimmune disease, and severe concurrent medical disease such as chronic obstructive pulmonary disease, congestive heart failure, or significant coronary artery disease.2, 6, 7 In addition to the negative impact on quality of life, adverse events and laboratory abnormalities often lead to dose reductions or discontinuation of IFN-α therapy, which further compromises efficacy.2, 3, 8, 9
IFN-λ1, also known as interleukin-29 (IL-29), is a type III IFN with functional similarities to type I IFNs, which include IFN-α and IFN-ß. Like IFN-α and IFN-ß, IFN-λ1 is induced in response to viral infections such as hepatitis C and has demonstrated antiviral activity in vitro, including inhibition of HCV RNA replication in the replicon model.10 IFN-λ1 interacts with the structurally unique IFN-λ1 receptor complex to stimulate an intracellular response through phosphorylation of the Janus kinase/signal transducer and activator of transcription pathway (similar to the mechanism of action of IFN-α) and leads to the up-regulation of IFN-stimulated genes and an antiviral effect.11, 12 Unlike the widely distributed IFN-α receptor, expression of the IFN-λ1 receptor is more restricted. Although all cell types in the liver express the IFN-α receptor, the IFN-λ1 receptor is found only in hepatocytes. Similarly, although all peripheral blood leukocytes, including B, T, and natural killer cells, neutrophils, and monocytes, express the IFN-α receptor, messenger RNA of the IFN-λ1 receptor is not expressed in hematopoietic cells with the exception of B lymphocytes.10, 13 The limited distribution of the IFN-λ1 receptor suggests the potential for reduced adverse events with IFN-λ1-based therapy in comparison with IFN-α-based therapy along with preservation of the antiviral effect in HCV.
PEG-IFN-λ, a conjugate of a recombinant form of human IFN-λ1 and a 20-kDa linear polyethylene glycol chain, is currently under development for the treatment of chronic HCV infection. A phase 1a, placebo-controlled, dose escalation study of single subcutaneous doses of PEG-IFN-λ in healthy subjects was recently completed.14 PEG-IFN-λ was well tolerated at pharmacologically active doses without the toxicities typically associated with PEG-IFN-α. The estimated half-life was 50 to 80 hours, and the time to the maximum concentration was 8 to 24 hours. PEG-IFN-λ, starting at the 1.5 µg/kg dose, demonstrated dose-dependent biological activity with the induction of increases in serum ß2-microglobulin (ß2M). Here we describe the results of a three-part study assessing the safety and antiviral activity of PEG-IFN-λ with or without RBV over 4 weeks in patients infected with genotype 1 chronic HCV.
Patients and Methods
Study Design.
This was a three-part dose and schedule escalation study of PEG-IFN-λ administered subcutaneously as a single agent or in combination with RBV in patients chronically infected with HCV genotype 1 who had relapsed after IFN-α-based treatment (parts 1 and 2) or who were naive to treatment (part 3). Part 1 of the study evaluated escalating doses of PEG-IFN-λ monotherapy administered either every 2 weeks (Q2W) or weekly (QW) for a total of 4 weeks. Parts 2 and 3 of this study evaluated a range of doses of PEG-IFN-λ administered QW in combination with RBV twice daily for 4 weeks. All patients were followed for at least 4 weeks after the completion of treatment.
Figure 1 summarizes the treatment schema for the three parts of the study. PEG-IFN-λ doses ranging from 0.5 to 3.0 µg/kg were evaluated. PEG-IFN-λ was supplied at a concentration of 10 mg/mL, and a two-step dilution was required to achieve the final dose for subcutaneous administration. No dose modifications were allowed. In parts 2 and 3, RBV (Copegus, Roche Laboratories, Inc., Nutley, NJ) was administered orally twice daily to achieve a total dose of 1000 mg for patients < 75 kg or 1200 mg for patients ≥ 75 kg. The primary endpoints of the study were safety and tolerability. Secondary endpoints included HCV RNA reduction and pharmacokinetic analysis of PEG-IFN-λ serum concentrations.
Each cohort consisted of at least six evaluable patients. To be considered evaluable, a patient had to have completed all study visits through day 29 (Q2W cohorts) or day 36 (QW cohorts) unless the reason for not doing so was PEG-IFN-λ-related toxicity. A dose level or schedule was considered not tolerated if two or more patients experienced dose-limiting toxicity (DLT) or if two or more patients were unable to receive all planned doses because of treatment-related toxicity. Data from each cohort were reviewed by a safety monitoring committee.
Patients.
Parts 1 and 2 enrolled patients with chronic HCV infection who had relapsed after at least 12 weeks of prior treatment for HCV with either PEG-IFN-α or another IFN-α in combination with RBV. Part 3 enrolled treatment-naive patients. Patients had HCV genotype 1 infection and serum HCV RNA levels ≥ 100,000 IU/mL at enrollment. Inclusion criteria included alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels ≤ 2.5 times the upper limit of normal with no evidence of decompensated liver disease or hepatocellular carcinoma and documented liver biopsy within 2 years of study enrollment with an Ishak score ≤ 4.15 Patients were excluded if they had significant cardiac disease or a medical condition requiring immunosuppressive therapy. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki and was consistent with good clinical practice guidelines and requirements of the regulatory authorities at each institution. All patients provided written, informed consent.
Safety Assessments.
All patients who received at least one dose of PEG-IFN-λ were included in the safety analyses. The evaluation of safety included adverse event monitoring, physical examination, clinical laboratories (hematology and serum chemistry), electrocardiogram, and echocardiogram. The National Cancer Institute's Common Terminology Criteria for Adverse Events (version 3.0) was used to evaluate adverse event severity and laboratory toxicities.
DLT included any clinical adverse event ≥ grade 3 in severity that was at least possibly related to PEG-IFN-λ treatment, with the exceptions of transient (<72-hour) grade 3 fatigue, fever, or rigor. In addition, a >5-fold increase in ALT or AST levels from the baseline (≥grade 2) or a >2-fold increase in ALT or AST levels from the baseline (≥grade 2) with a grade 2 elevation in bilirubin was considered DLT. If the ALT or AST level increased to more than 3 times the baseline (≥grade 2) or more than 7 times the upper limit of normal, but the bilirubin level or international normalized ratio did not increase to grade 2, PEG-IFN-λ was to be held until the ALT or AST level returned to less than 2 times the baseline value.
Pharmacokinetics.
Pharmacokinetic samples were collected at selected time points throughout the study. Samples were analyzed with a fully validated method developed at ZymoGenetics with mesoscale discovery electrochemiluminescent technology to quantify the PEG-IFN-λ serum concentration. The lower limit of quantification of the assay was 0.125 ng/mL in human serum. The PEG-IFN-λ serum concentration versus time profile for each patient was evaluated by noncompartmental methods with the software WinNonlin 5.2.1 (Pharsight Corp., Cary, NC). The maximum serum concentration (Cmax) and the area under the curve (AUC0-t) were estimated for each patient.
Immunogenicity.
Serum samples for evaluating antibody responses directed against PEG-IFN-λ were collected and analyzed with a fully validated method developed at ZymoGenetics with mesoscale discovery electrochemiluminescent technology to detect antibodies to PEG-IFN-λ1. Analysis was performed by a tiered approach designed to confirm reactivity, quantify the antibody titer, and demonstrate specificity. Samples that were confirmed to be reactive and demonstrated specificity to the drug product were assayed for neutralizing activity in a cell-based assay. The lower limit of assay detection was 0.1 µg/mL. The cell-based neutralizing bioassay was qualitative in nature.
Pharmacodynamics.
Samples were collected for pharmacodynamic studies at selected time points during the study. ß2M levels were assessed with a competitive binding assay (R&D Systems, Minneapolis, MN). The lower limit of assay quantification was 0.4 µg/mL.
Efficacy Assessments.
HCV RNA levels were measured with the COBAS TaqMan HCV test (version 2.0, Roche Molecular Diagnostics, Pleasanton, CA) with a lower limit of detection of 25 IU/mL. A central laboratory with expertise in the serial measurement of HCV RNA levels was used (Covance, Indianapolis, IN).
Data Analysis Methods.
No formal hypothesis was proposed; however, a cohort size of six patients would allow for a greater than 80% probability of detecting an event with a true population incidence of 25% and allow an evaluation of antiviral activity. The presented data represent an intent-to-treat population. All statistical analyses were performed with SAS (version 9.1.3 or higher, SAS Institute, Inc., Cary, NC) or other commercially available validated software.
RESULTS
Patient Demographics and Baseline Characteristics.
Fifty-six patients were enrolled from 10 sites in the United States: 24 with treatment-relapse disease in part 1, 25 with treatment-relapse disease in part 2, and 7 with treatment-naive disease in part 3 (Fig. 1). All but one patient completed the study through day 59. One patient in the cohort receiving 1.5 µg/kg PEG-IFN-λ QW plus RBV discontinued dosing after receiving PEG-IFN-λ through day 8 because of an adverse drug reaction to meperidine that was deemed unrelated to PEG-IFN-λ. Data from this patient were excluded from the efficacy assessment.
Patient demographics are shown in Table 1. All treatment-relapse patients had received at least one previous course of therapy with a PEG-IFN-α plus RBV except for two patients, one of whom had previously received treatment with albinterferon alfa-2b plus RBV and one of whom had previously received interferon alfacon-1.
Safety and Tolerability.
PEG-IFN-λ was well tolerated by most patients. Four of 56 patients (7%) had one or more doses withheld because of treatment-related toxicity. Most adverse events were mild or moderate in severity. Table 2 summarizes adverse events occurring in at least three patients in all cohorts combined. The most common adverse events were fatigue (29%), nausea (12%), myalgia (11%), and headache (9%). Among treatment-relapse patients, fatigue, nausea, myalgia, headache, diarrhea, irritability, pruritis, and insomnia were more commonly observed in patients treated with PEG-IFN-λ in combination with RBV versus those receiving single-agent therapy. PEG-IFN-λ plus RBV therapy was very well tolerated by treatment-naive patients, with fatigue, headache, and chills each reported by one of seven patients (14%) and with no patients reporting nausea, myalgia, diarrhea, irritability, pruritis, anorexia, influenza-like illness, or insomnia. The incidence of adverse events did not appear to be dose-related; adverse events were reported in 33.3%, 50%, 50%, and 50% of patients in part 1 cohorts receiving 1.5 µg/kg PEG-IFN-λ Q2W, 3.0 µg/kg PEG-IFN-λ Q2W, 1.5 µg/kg PEG-IFN-λ QW, and 3.0 µg/kg PEG-IFN-λ QW, respectively. Similarly, in part 2 (PEG-IFN-λ plus RBV), adverse events were reported in 83.3%, 83.3%, 85.7%, and 83.3% of patients receiving 0.5 µg/kg PEG-IFN-λ Q2W, 0.75 µg/kg PEG-IFN-λ Q2W, 1.5 µg/kg PEG-IFN-λ QW, and 2.25 µg/kg PEG-IFN-λ QW, respectively. Adverse events were reported in 42.9% of treatment-naive patients receiving 1.5 µg/kg PEG-IFN-λ QW plus RBV.
Clinical Laboratory Evaluations.
Five patients experienced aminotransferase elevations that met the protocol-defined criteria for DLT, and an additional patient met the criteria for temporarily holding of a dose of PEG-IFN-λ (Table 3). Of these patients, four were in cohorts receiving the highest PEG-IFN-λ dose evaluated [3.0 µg/kg QW (n = 3) or Q2W (n = 1)], and two were in cohorts receiving 1.5 µg/kg PEG-IFN-λ QW with RBV (n = 1) or without RBV (n = 1). In three patients, the ALT and AST elevations were accompanied by a bilirubin elevation. All elevations in ALT, AST, and bilirubin were reversible, generally at or before the end of the study visit (day 59).
Grade 3 or 4 elevations in lipase and/or amylase not associated with abdominal pain or nausea were observed in four patients during the study; all were resolved after the withholding or discontinuation of PEG-IFN-λ. One patient had the day 15 dose held and was subsequently successfully treated on day 22, with no loss of antiviral effect observed that was related to the interruption. No other clinically important changes were noted in serum chemistry values.
Mean absolute neutrophil counts and platelet counts over time in cohorts receiving PEG-IFN-λ plus RBV are displayed in Fig. 2(A1,A2), respectively. There were no clinically significant changes in absolute neutrophil counts. Three patients with baseline absolute neutrophil counts in the low normal range of 2.04 to 2.30 x 109/L had decreases to 1.62 to 1.80 x 109/L; these were all isolated values that required no change in the studied therapy. One patient (described previously) experienced a grade 3 decrease in platelets during the posttreatment follow-up period, and this was concurrent with a diagnosis of idiopathic thrombocytopenic purpura; platelet decreases were not observed in other patients. Figure 2(B1,B2) displays the mean hemoglobin values in the cohorts that received PEG-IFN-λ as a single agent and PEG-IFN-λ plus RBV, respectively. No significant changes were observed in patients treated with single-agent PEG-IFN-λ, whereas decreases in hemoglobin consistent with the known effects of RBV were observed in patients treated with combination therapy.
Antiviral Activity.
Virological responses are summarized in Table 4. Antiviral activity was observed at all PEG-IFN-λ dose levels. Among the 43 patients dosed QW and evaluable for efficacy, all but 4 achieved a >1-log10 decline in HCV RNA during the study. The first day of treatment yielded a rapid decline in HCV RNA that continued in a biphasic manner from days 4 through 29; this was similar to the pattern observed with IFN-α.16 Higher PEG-IFN-λ doses were associated with greater declines in HCV RNA when PEG-IFN-λ was used both as a single agent and in combination with RBV (Fig. 3). At PEG-IFN-λ doses ≥ 1.5 µg/kg QW with or without RBV, 23 of 24 treatment-relapse patients (96%) achieved a >2-log10 decline in HCV RNA levels, and 4 of 24 (17%) achieved undetectable HCV RNA. Among treatment-naive patients, six of seven patients (86%) achieved a >2-log10 decline in HCV RNA levels, and they included two (29%) who achieved undetectable HCV RNA. Among patients dosed QW with PEG-IFN-λ with or without RBV, a >2-log10 decline in HCV was achieved by 21 of 28 white patients (75%), 8 of 8 African American patients (100%), and 6 of 7 Hispanic patients (86%).
Four treatment-relapse patients who received PEG-IFN-λ QW did not achieve a >1-log10 reduction in HCV RNA. Three of these patients were in the lowest PEG-IFN-λ dose cohorts; two were treated with 0.5 µg/kg PEG-IFN-λ QW plus RBV, and one was treated with 0.75 µg/kg PEG-IFN-λ QW plus RBV. The remaining patient without a detectable antiviral response was treated with 1.5 µg/kg PEG-IFN-λ QW plus RBV; this patient had preexisting neutralizing antibodies against PEG-IFN-λ and very low or undetectable serum levels of the study drug throughout the study period.
Pharmacokinetics.
The first-dose Cmax and AUC0-t values are summarized in Table 5. Two patients were excluded from the pharmacokinetic analyses; one patient who received PEG-IFN-λ (1.5 µg/kg) was excluded because of premature discontinuation of the study, and one patient who received 0.5 µg/kg PEG-IFN-λ was excluded because of Cmax and AUC0-t values grossly inconsistent with the nominal dose administered.
Overall, the exposure of PEG-IFN-λ appeared to be dose-dependent and ranged from a mean AUC0-t value of 11.6 h*ng/mL at the 0.5 µg/kg dose level to 148 h*ng/mL at the 3.0 mg/kg dose level. Normalization of AUC0-t by dose (µg/kg) appeared to remove the effect of dose on exposure, and this suggested that exposure may increase linearly with dose. A modest accumulation from week 1 to week 4 was observed with average patient Cmax and AUC0-t accumulation index values of 1.12 and 1.34, respectively. No obvious effect of RBV on the exposure to PEG-IFN-λ was detected. To explore the effect of body weight on exposure, AUC0-t/dose (µg) estimates were compared to the body weight. No trend was detected, and linear regression analysis indicated no apparent effect of weight on exposure.
Although there was no continuous relationship between exposure and change in ALT, very high exposure was observed in patients who demonstrated significant ALT elevations. Among patients dosed QW, six had a PEG-IFN-λ AUC0-t value > 225 h ng/mL; four of these patients (67%) experienced DLT. Conversely, there appeared to be a continuous relationship between PEG-IFN-λ exposure and decreases in HCV RNA, with robust antiviral activity observed at exposures both above and below 225 h*ng/mL (Fig. 4).
Pharmacodynamics.
A rapid rise in ß2M levels was observed after the first dose of PEG-IFN-λ; levels peaked on day 4 and decreased toward the baseline values by day 8. Increases in ß2M were observed at all dose levels, and this confirmed pharmacological activity. A potential relationship between ß2M induction and decreases in HCV RNA was observed. In general, patients who had the greatest HCV RNA decline on day 8 had the strongest induction of ß2M. In addition, minimal or no induction of ß2M was observed in patients with only minimal changes in HCV RNA on day 8, and this suggested that the lack of a virological response in these patients was likely related to an absence of pharmacological activity.
Immunogenicity.
Low-titer antibodies specific to PEG-IFN-λ developed in 3 of 56 patients (5.4%) during the study (all in the treatment-relapse group). Neutralizing activity was observed on day 59 in one of these patients (1.8%); this patient achieved a ≥2-log decrease from the baseline in HCV RNA on days 22 and 29.
Two additional treatment-relapse patients had detectable antibodies to PEG-IFN-λ prior to treatment and throughout the study period; neither had a titer increase during the study. One of these patients had neutralizing antibodies and had very low or unmeasurable PEG-IFN-λ serum levels and no antiviral response throughout the study period. The second patient had preexisting but nonneutralizing antibodies to PEG-IFN-λ and had measurable serum levels of PEG-IFN-λ as well as an antiviral response (a 3.81-log10 decrease on day 29).
DISCUSSION
This study was the first designed to assess the safety, tolerability, and efficacy of PEG-IFN-λ in patients chronically infected with genotype 1 HCV. The results indicate that a broad range of PEG-IFN-λ doses exhibit antiviral activity with limited toxicity when it is administered QW, and this supports the hypothesis that PEG-IFN-λ may be a useful agent in future HCV treatment regimens
SVR, the most definitive measure of antiviral activity, was not evaluated in this study because patients received only 4 weeks of therapy with PEG-IFN-λ with or without RBV. However, relationships between early viral kinetics and long-term response are well established and add clinical relevance to the 4-week antiviral results observed in the current study. Predictive markers of response, including rapid virological response (defined as undetectable HCV RNA at week 4) and early virological response (defined as a >2-log10 decrease in HCV RNA by week 12), have been demonstrated to predict response in treatment-naive patients treated with PEG-IFN-α plus RBV and in treatment-relapse patients as well.17-21 A recent report demonstrated that a ≥2-log10 decrease in HCV RNA by week 4 had a positive predictive value of 52% and a negative predictive value of 94% for predicting SVR in treatment-relapse patients receiving PEG-IFN-α in combination with RBV.19
Parts 1 and 2 of the study included patients who had previously responded to therapy with PEG-IFN-α, and this allowed a close examination of the safety profile in a group of patients who were expected to demonstrate antiviral activity (proof of concept) within a short treatment period. As anticipated, antiviral activity was observed in the majority of treatment-relapse patients, especially in those who received a dose of PEG-IFN-λ ≥ 1.5 µg/kg QW with or without RBV, with 23 of 24 patients (96%) achieving at least a >2-log10 decrease in HCV RNA. Although information on the viral kinetics of the patients' previous responses to IFN-α-based therapies was not collected as part of the study, this magnitude of HCV RNA decrease in the first 4 weeks of therapy indicates clear antiviral activity potentially comparable to that of PEG-IFN-α.
Unambiguous antiviral activity was also observed in the cohort of treatment-naive patients who were all treated with 1.5 µg/kg PEG-IFN-λ QW plus RBV. Six of the seven treatment-naive patients (86%) achieved a >2-log10 decrease in HCV RNA, and two of seven (29%) achieved undetectable HCV RNA; this was an encouraging result despite the small sample size. Historically published rates of >2-log10 decreases in HCV RNA or undetectable HCV RNA after 4 weeks of therapy with PEG-IFN-α plus RBV in treatment-naive patients range from 42% to 67% and from 7.4% to 11.7%, respectively.3, 16, 22
Recent evidence indicates that the viral response to PEG-IFN-α plus RBV may have a genetic basis.23, 24 Single nucleotide polymorphisms upstream from the IL-28B gene on chromosome 19 have been found to be associated with SVR to PEG-IFN-α plus RBV treatment as well as natural clearance of HCV infection.23-27 These links to IL-28B were initially found through genome-wide association studies, so the mechanism of action was not determined. The connection to PEG-IFN-λ is of interest because IL-28B is also a type III IFN known as IFN-λ3, which shares approximately 70% sequence identity with IFN-λ1 and shares the same receptor with IFN-λ1. The genes for IFN-λ1 (IL-29), IFN-λ2 (IL-28A), and IFN-λ3 (IL-28B) are all located in this same region of chromosome 19. It is possible that the IFN-λ family has unique antiviral effects important to the control of HCV infection, and studies to assess the impact of the different polymorphisms on the antiviral response to PEG-IFN-λ plus RBV are being conducted.
Overall, PEG-IFN-λ, given QW for 4 weeks, was safe and was well tolerated by most patients. Minimal constitutional symptoms or hematologic effects were observed with PEG-IFN-λ as a single agent. As expected, the addition of RBV increased the incidence of fatigue and other constitutional symptoms in treatment-relapse patients. Previously untreated patients experienced a low incidence of adverse events, despite combination therapy with RBV, and this suggested a possible experience effect from previous treatment in the treatment-relapse patients. The majority of significant aminotransferase elevations occurred in patients with high PEG-IFN-λ exposure values, which were well above the mean for the individual cohorts. Dose reductions were not allowed in the current study. However, because the aminotransferase elevations were reversible and may be related to high exposure, it may be possible in future studies to manage these effects with dose reductions.
Pharmacokinetic data suggest that the relationship between dose and exposure may be linear and that body weight is not an important determinant of exposure. Future studies will explore fixed microgram doses of PEG-IFN-λ; this is expected to be less complicated for self-administration than weight-based dosing. In addition, the use of a ready-to-use formulation in future studies may also reduce the interpatient variability in PEG-IFN-λ exposure estimates.
Only one patient developed a neutralizing antibody to PEG-IFN-λ during the study. Because the antibody was not observed until day 59, 4 weeks after the last dose of PEG-IFN-λ, no conclusions can be drawn regarding a potential effect on the PEG-IFN-λ serum concentration or antiviral activity. The incidence of neutralizing antibody formation with PEG-IFN-α is approximately 2% to 3%, although direct comparisons between different products may not be valid because the observed incidence of antibody positivity is highly dependent on the sensitivity of the assay.5, 6
These safety and tolerability results observed with the 4-week PEG-IFN-λ treatment compare favorably with the results of published studies of 48-week PEG-IFN-α therapy, in which up to 67% of patients have experienced fatigue, 62% have experienced headache, 56% have experienced myalgia, 48% have experienced rigors, 46% have experienced fever, 43% have experienced nausea, and 40% have experienced insomnia.3, 28 Although direct comparisons with the safety of PEG-IFN-α therapy are not possible because of the 4-week treatment duration in the current study, the incidence of constitutional side effects observed with PEG-IFN-λ therapy appears to be lower. The myelosuppression associated with IFN-α treatment is related to its binding to leukocytes.29 Although adverse hematologic events may appear after 4 weeks of therapy, the absence of IFN-λ binding to leukocytes may explain why such adverse effects have not yet been observed with PEG-IFN-λ therapy.
Key limitations in the current study include the lack of a direct comparison between PEG-IFN-λ and PEG-IFN-α, and this restricts any conclusions regarding the relative effects of one agent with respect to the other. Because the current study encompassed only 4 weeks of dosing, the long-term effects of PEG-IFN-λ could not be determined. The open-label design of the study may have influenced adverse event reporting. Lastly, the study included only patients with genotype 1 HCV infection, and it is not known if these results will translate to patients with other genotypes. Future studies will explore these questions.
The findings from this study offer evidence that PEG-IFN-λ, given QW for 4 weeks, exhibits potent antiviral effects against HCV with the potential for an improved tolerability profile with respect to that traditionally observed for PEG-IFN-α. These results are being tested in larger randomized controlled trials enrolling treatment-naive patients.
Source
Andrew J. Muir 1,2,*,, Mitchell L. Shiffman 3, Atif Zaman 4, Boris Yoffe 5, Andrew de la Torre 6, Steven Flamm 7, Stuart C. Gordon 8, Paul Marotta 9, John M. Vierling 10, Juan Carlos Lopez-Talavera 11, Kelly Byrnes-Blake 12, David Fontana 12, Jeremy Freeman 12, Todd Gray 12, Diana Hausman 12, Naomi N. Hunder 12, Eric Lawitz 13
Hepatology Article first published online: 14 MAY 2010
"The findings from this study offer evidence that PEG-IFN-λ, given QW for 4 weeks, exhibits potent antiviral effects against HCV with the potential for an improved tolerability profile with respect to that traditionally observed for PEG-IFN-α. These results are being tested in larger randomized controlled trials enrolling treatment-naive patients."
ABSTRACT
Interferon lambda 1 (IFN-λ1) is a type III IFN that produces intracellular responses similar to those of IFN-α but in fewer cell types because of differences in the receptor distribution pattern, and this could potentially result in an improved safety profile. This was an open-label three-part study of patients with chronic hepatitis C virus (HCV) genotype 1 infection. Part 1 evaluated single-agent pegylated interferon lambda (PEG-IFN-λ) at 1.5 or 3.0 µg/kg administered every 2 weeks or weekly for 4 weeks in patients who had relapsed after previous IFN-α-based treatment. Part 2 evaluated weekly doses of PEG-IFN-λ ranging from 0.5 to 2.25 µg/kg in combination with ribavirin (RBV) for 4 weeks in treatment-relapse patients. Part 3 evaluated weekly PEG-IFN-λ at 1.5 µg/kg in combination with RBV for 4 weeks in treatment-naive patients. Fifty-six patients were enrolled: 24 patients in part 1, 25 patients in part 2, and 7 patients in part 3. Antiviral activity was observed at all PEG-IFN-λ dose levels (from 0.5 to 3.0 µg/kg). Two of seven treatment-naive patients (29%) achieved rapid virological response. Treatment was well tolerated with minimal flu-like symptoms and no significant hematologic changes other than RBV-associated decreases in hemoglobin. The most common adverse events were fatigue (29%), nausea (12%), and myalgia (11%). Six patients experienced increases in aminotransferases that met protocol-defined criteria for dose-limiting toxicity (DLT) or temporarily holding therapy with PEG-IFN-λ. Most DLT occurred in patients with high PEG-IFN-λ exposure. Conclusion: Weekly PEG-IFN-λ with or without daily RBV for 4 weeks is well tolerated with minimal adverse events and hematologic effects and is associated with clear antiviral activity across a broad range of doses in patients with chronic HCV. (HEPATOLOGY 2010;)
The World Health Organization estimates that 180 million people worldwide (3% of the world population) are infected with hepatitis C virus (HCV), and 130 million of these are chronic HCV carriers.1 Chronic HCV infection is responsible for 50% to 76% of all liver cancer cases, two-thirds of all liver transplants in the developed world, and considerable morbidity and mortality. Identifying effective treatments for chronic HCV infection is therefore a global health priority.1
Consensus guidelines for the treatment of hepatitis C recommend a regimen of pegylated interferon alfa (PEG-IFN-α) and ribavirin (RBV).2 However, this treatment regimen results in sustained virological response (SVR) rates of only 40% in patients with genotype 1 HCV, and associated adverse events include flu-like symptoms, fatigue, depression, anxiety, and bone marrow suppression, which results in anemia, neutropenia, and thrombocytopenia.2-6 PEG-IFN-α is contraindicated in patients with major uncontrolled depressive illness and should be used with caution in patients with any psychiatric illness.2, 5-7 Other contraindications for the use of interferon alpha (IFN-α)-based regimens include hepatic decompensation, autoimmune disease, and severe concurrent medical disease such as chronic obstructive pulmonary disease, congestive heart failure, or significant coronary artery disease.2, 6, 7 In addition to the negative impact on quality of life, adverse events and laboratory abnormalities often lead to dose reductions or discontinuation of IFN-α therapy, which further compromises efficacy.2, 3, 8, 9
IFN-λ1, also known as interleukin-29 (IL-29), is a type III IFN with functional similarities to type I IFNs, which include IFN-α and IFN-ß. Like IFN-α and IFN-ß, IFN-λ1 is induced in response to viral infections such as hepatitis C and has demonstrated antiviral activity in vitro, including inhibition of HCV RNA replication in the replicon model.10 IFN-λ1 interacts with the structurally unique IFN-λ1 receptor complex to stimulate an intracellular response through phosphorylation of the Janus kinase/signal transducer and activator of transcription pathway (similar to the mechanism of action of IFN-α) and leads to the up-regulation of IFN-stimulated genes and an antiviral effect.11, 12 Unlike the widely distributed IFN-α receptor, expression of the IFN-λ1 receptor is more restricted. Although all cell types in the liver express the IFN-α receptor, the IFN-λ1 receptor is found only in hepatocytes. Similarly, although all peripheral blood leukocytes, including B, T, and natural killer cells, neutrophils, and monocytes, express the IFN-α receptor, messenger RNA of the IFN-λ1 receptor is not expressed in hematopoietic cells with the exception of B lymphocytes.10, 13 The limited distribution of the IFN-λ1 receptor suggests the potential for reduced adverse events with IFN-λ1-based therapy in comparison with IFN-α-based therapy along with preservation of the antiviral effect in HCV.
PEG-IFN-λ, a conjugate of a recombinant form of human IFN-λ1 and a 20-kDa linear polyethylene glycol chain, is currently under development for the treatment of chronic HCV infection. A phase 1a, placebo-controlled, dose escalation study of single subcutaneous doses of PEG-IFN-λ in healthy subjects was recently completed.14 PEG-IFN-λ was well tolerated at pharmacologically active doses without the toxicities typically associated with PEG-IFN-α. The estimated half-life was 50 to 80 hours, and the time to the maximum concentration was 8 to 24 hours. PEG-IFN-λ, starting at the 1.5 µg/kg dose, demonstrated dose-dependent biological activity with the induction of increases in serum ß2-microglobulin (ß2M). Here we describe the results of a three-part study assessing the safety and antiviral activity of PEG-IFN-λ with or without RBV over 4 weeks in patients infected with genotype 1 chronic HCV.
Patients and Methods
Study Design.
This was a three-part dose and schedule escalation study of PEG-IFN-λ administered subcutaneously as a single agent or in combination with RBV in patients chronically infected with HCV genotype 1 who had relapsed after IFN-α-based treatment (parts 1 and 2) or who were naive to treatment (part 3). Part 1 of the study evaluated escalating doses of PEG-IFN-λ monotherapy administered either every 2 weeks (Q2W) or weekly (QW) for a total of 4 weeks. Parts 2 and 3 of this study evaluated a range of doses of PEG-IFN-λ administered QW in combination with RBV twice daily for 4 weeks. All patients were followed for at least 4 weeks after the completion of treatment.
Figure 1 summarizes the treatment schema for the three parts of the study. PEG-IFN-λ doses ranging from 0.5 to 3.0 µg/kg were evaluated. PEG-IFN-λ was supplied at a concentration of 10 mg/mL, and a two-step dilution was required to achieve the final dose for subcutaneous administration. No dose modifications were allowed. In parts 2 and 3, RBV (Copegus, Roche Laboratories, Inc., Nutley, NJ) was administered orally twice daily to achieve a total dose of 1000 mg for patients < 75 kg or 1200 mg for patients ≥ 75 kg. The primary endpoints of the study were safety and tolerability. Secondary endpoints included HCV RNA reduction and pharmacokinetic analysis of PEG-IFN-λ serum concentrations.
Each cohort consisted of at least six evaluable patients. To be considered evaluable, a patient had to have completed all study visits through day 29 (Q2W cohorts) or day 36 (QW cohorts) unless the reason for not doing so was PEG-IFN-λ-related toxicity. A dose level or schedule was considered not tolerated if two or more patients experienced dose-limiting toxicity (DLT) or if two or more patients were unable to receive all planned doses because of treatment-related toxicity. Data from each cohort were reviewed by a safety monitoring committee.
Patients.
Parts 1 and 2 enrolled patients with chronic HCV infection who had relapsed after at least 12 weeks of prior treatment for HCV with either PEG-IFN-α or another IFN-α in combination with RBV. Part 3 enrolled treatment-naive patients. Patients had HCV genotype 1 infection and serum HCV RNA levels ≥ 100,000 IU/mL at enrollment. Inclusion criteria included alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels ≤ 2.5 times the upper limit of normal with no evidence of decompensated liver disease or hepatocellular carcinoma and documented liver biopsy within 2 years of study enrollment with an Ishak score ≤ 4.15 Patients were excluded if they had significant cardiac disease or a medical condition requiring immunosuppressive therapy. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki and was consistent with good clinical practice guidelines and requirements of the regulatory authorities at each institution. All patients provided written, informed consent.
Safety Assessments.
All patients who received at least one dose of PEG-IFN-λ were included in the safety analyses. The evaluation of safety included adverse event monitoring, physical examination, clinical laboratories (hematology and serum chemistry), electrocardiogram, and echocardiogram. The National Cancer Institute's Common Terminology Criteria for Adverse Events (version 3.0) was used to evaluate adverse event severity and laboratory toxicities.
DLT included any clinical adverse event ≥ grade 3 in severity that was at least possibly related to PEG-IFN-λ treatment, with the exceptions of transient (<72-hour) grade 3 fatigue, fever, or rigor. In addition, a >5-fold increase in ALT or AST levels from the baseline (≥grade 2) or a >2-fold increase in ALT or AST levels from the baseline (≥grade 2) with a grade 2 elevation in bilirubin was considered DLT. If the ALT or AST level increased to more than 3 times the baseline (≥grade 2) or more than 7 times the upper limit of normal, but the bilirubin level or international normalized ratio did not increase to grade 2, PEG-IFN-λ was to be held until the ALT or AST level returned to less than 2 times the baseline value.
Pharmacokinetics.
Pharmacokinetic samples were collected at selected time points throughout the study. Samples were analyzed with a fully validated method developed at ZymoGenetics with mesoscale discovery electrochemiluminescent technology to quantify the PEG-IFN-λ serum concentration. The lower limit of quantification of the assay was 0.125 ng/mL in human serum. The PEG-IFN-λ serum concentration versus time profile for each patient was evaluated by noncompartmental methods with the software WinNonlin 5.2.1 (Pharsight Corp., Cary, NC). The maximum serum concentration (Cmax) and the area under the curve (AUC0-t) were estimated for each patient.
Immunogenicity.
Serum samples for evaluating antibody responses directed against PEG-IFN-λ were collected and analyzed with a fully validated method developed at ZymoGenetics with mesoscale discovery electrochemiluminescent technology to detect antibodies to PEG-IFN-λ1. Analysis was performed by a tiered approach designed to confirm reactivity, quantify the antibody titer, and demonstrate specificity. Samples that were confirmed to be reactive and demonstrated specificity to the drug product were assayed for neutralizing activity in a cell-based assay. The lower limit of assay detection was 0.1 µg/mL. The cell-based neutralizing bioassay was qualitative in nature.
Pharmacodynamics.
Samples were collected for pharmacodynamic studies at selected time points during the study. ß2M levels were assessed with a competitive binding assay (R&D Systems, Minneapolis, MN). The lower limit of assay quantification was 0.4 µg/mL.
Efficacy Assessments.
HCV RNA levels were measured with the COBAS TaqMan HCV test (version 2.0, Roche Molecular Diagnostics, Pleasanton, CA) with a lower limit of detection of 25 IU/mL. A central laboratory with expertise in the serial measurement of HCV RNA levels was used (Covance, Indianapolis, IN).
Data Analysis Methods.
No formal hypothesis was proposed; however, a cohort size of six patients would allow for a greater than 80% probability of detecting an event with a true population incidence of 25% and allow an evaluation of antiviral activity. The presented data represent an intent-to-treat population. All statistical analyses were performed with SAS (version 9.1.3 or higher, SAS Institute, Inc., Cary, NC) or other commercially available validated software.
RESULTS
Patient Demographics and Baseline Characteristics.
Fifty-six patients were enrolled from 10 sites in the United States: 24 with treatment-relapse disease in part 1, 25 with treatment-relapse disease in part 2, and 7 with treatment-naive disease in part 3 (Fig. 1). All but one patient completed the study through day 59. One patient in the cohort receiving 1.5 µg/kg PEG-IFN-λ QW plus RBV discontinued dosing after receiving PEG-IFN-λ through day 8 because of an adverse drug reaction to meperidine that was deemed unrelated to PEG-IFN-λ. Data from this patient were excluded from the efficacy assessment.
Patient demographics are shown in Table 1. All treatment-relapse patients had received at least one previous course of therapy with a PEG-IFN-α plus RBV except for two patients, one of whom had previously received treatment with albinterferon alfa-2b plus RBV and one of whom had previously received interferon alfacon-1.
Safety and Tolerability.
PEG-IFN-λ was well tolerated by most patients. Four of 56 patients (7%) had one or more doses withheld because of treatment-related toxicity. Most adverse events were mild or moderate in severity. Table 2 summarizes adverse events occurring in at least three patients in all cohorts combined. The most common adverse events were fatigue (29%), nausea (12%), myalgia (11%), and headache (9%). Among treatment-relapse patients, fatigue, nausea, myalgia, headache, diarrhea, irritability, pruritis, and insomnia were more commonly observed in patients treated with PEG-IFN-λ in combination with RBV versus those receiving single-agent therapy. PEG-IFN-λ plus RBV therapy was very well tolerated by treatment-naive patients, with fatigue, headache, and chills each reported by one of seven patients (14%) and with no patients reporting nausea, myalgia, diarrhea, irritability, pruritis, anorexia, influenza-like illness, or insomnia. The incidence of adverse events did not appear to be dose-related; adverse events were reported in 33.3%, 50%, 50%, and 50% of patients in part 1 cohorts receiving 1.5 µg/kg PEG-IFN-λ Q2W, 3.0 µg/kg PEG-IFN-λ Q2W, 1.5 µg/kg PEG-IFN-λ QW, and 3.0 µg/kg PEG-IFN-λ QW, respectively. Similarly, in part 2 (PEG-IFN-λ plus RBV), adverse events were reported in 83.3%, 83.3%, 85.7%, and 83.3% of patients receiving 0.5 µg/kg PEG-IFN-λ Q2W, 0.75 µg/kg PEG-IFN-λ Q2W, 1.5 µg/kg PEG-IFN-λ QW, and 2.25 µg/kg PEG-IFN-λ QW, respectively. Adverse events were reported in 42.9% of treatment-naive patients receiving 1.5 µg/kg PEG-IFN-λ QW plus RBV.
Two patients experienced other clinically important events considered related to PEG-IFN-λ. One patient treated with 3.0 µg/kg PEG-IFN-λ QW as a single agent experienced grade 3 idiopathic thrombocytopenic purpura, which occurred 2 weeks after the final dose; this event was considered DLT. The patient responded rapidly to therapy with oral prednisone. Another patient, treated with 1.5 µg/kg PEG-IFN-λ QW plus RBV in part 2, experienced elevated ALT, AST, and bilirubin levels, which met the protocol-defined criteria for withdrawing therapy. However, this patient received an additional dose of PEG-IFN-λ in violation of the protocol and subsequently experienced further elevation of ALT, AST, and bilirubin levels, which resulted in suspected medication-associated hepatotoxicity, pruritis, and elevated lipase and amylase levels (without associated clinical symptoms of pancreatitis).
Clinical Laboratory Evaluations.
Five patients experienced aminotransferase elevations that met the protocol-defined criteria for DLT, and an additional patient met the criteria for temporarily holding of a dose of PEG-IFN-λ (Table 3). Of these patients, four were in cohorts receiving the highest PEG-IFN-λ dose evaluated [3.0 µg/kg QW (n = 3) or Q2W (n = 1)], and two were in cohorts receiving 1.5 µg/kg PEG-IFN-λ QW with RBV (n = 1) or without RBV (n = 1). In three patients, the ALT and AST elevations were accompanied by a bilirubin elevation. All elevations in ALT, AST, and bilirubin were reversible, generally at or before the end of the study visit (day 59).
Grade 3 or 4 elevations in lipase and/or amylase not associated with abdominal pain or nausea were observed in four patients during the study; all were resolved after the withholding or discontinuation of PEG-IFN-λ. One patient had the day 15 dose held and was subsequently successfully treated on day 22, with no loss of antiviral effect observed that was related to the interruption. No other clinically important changes were noted in serum chemistry values.
Mean absolute neutrophil counts and platelet counts over time in cohorts receiving PEG-IFN-λ plus RBV are displayed in Fig. 2(A1,A2), respectively. There were no clinically significant changes in absolute neutrophil counts. Three patients with baseline absolute neutrophil counts in the low normal range of 2.04 to 2.30 x 109/L had decreases to 1.62 to 1.80 x 109/L; these were all isolated values that required no change in the studied therapy. One patient (described previously) experienced a grade 3 decrease in platelets during the posttreatment follow-up period, and this was concurrent with a diagnosis of idiopathic thrombocytopenic purpura; platelet decreases were not observed in other patients. Figure 2(B1,B2) displays the mean hemoglobin values in the cohorts that received PEG-IFN-λ as a single agent and PEG-IFN-λ plus RBV, respectively. No significant changes were observed in patients treated with single-agent PEG-IFN-λ, whereas decreases in hemoglobin consistent with the known effects of RBV were observed in patients treated with combination therapy.
Antiviral Activity.
Virological responses are summarized in Table 4. Antiviral activity was observed at all PEG-IFN-λ dose levels. Among the 43 patients dosed QW and evaluable for efficacy, all but 4 achieved a >1-log10 decline in HCV RNA during the study. The first day of treatment yielded a rapid decline in HCV RNA that continued in a biphasic manner from days 4 through 29; this was similar to the pattern observed with IFN-α.16 Higher PEG-IFN-λ doses were associated with greater declines in HCV RNA when PEG-IFN-λ was used both as a single agent and in combination with RBV (Fig. 3). At PEG-IFN-λ doses ≥ 1.5 µg/kg QW with or without RBV, 23 of 24 treatment-relapse patients (96%) achieved a >2-log10 decline in HCV RNA levels, and 4 of 24 (17%) achieved undetectable HCV RNA. Among treatment-naive patients, six of seven patients (86%) achieved a >2-log10 decline in HCV RNA levels, and they included two (29%) who achieved undetectable HCV RNA. Among patients dosed QW with PEG-IFN-λ with or without RBV, a >2-log10 decline in HCV was achieved by 21 of 28 white patients (75%), 8 of 8 African American patients (100%), and 6 of 7 Hispanic patients (86%).
Four treatment-relapse patients who received PEG-IFN-λ QW did not achieve a >1-log10 reduction in HCV RNA. Three of these patients were in the lowest PEG-IFN-λ dose cohorts; two were treated with 0.5 µg/kg PEG-IFN-λ QW plus RBV, and one was treated with 0.75 µg/kg PEG-IFN-λ QW plus RBV. The remaining patient without a detectable antiviral response was treated with 1.5 µg/kg PEG-IFN-λ QW plus RBV; this patient had preexisting neutralizing antibodies against PEG-IFN-λ and very low or undetectable serum levels of the study drug throughout the study period.
Pharmacokinetics.
The first-dose Cmax and AUC0-t values are summarized in Table 5. Two patients were excluded from the pharmacokinetic analyses; one patient who received PEG-IFN-λ (1.5 µg/kg) was excluded because of premature discontinuation of the study, and one patient who received 0.5 µg/kg PEG-IFN-λ was excluded because of Cmax and AUC0-t values grossly inconsistent with the nominal dose administered.
Overall, the exposure of PEG-IFN-λ appeared to be dose-dependent and ranged from a mean AUC0-t value of 11.6 h*ng/mL at the 0.5 µg/kg dose level to 148 h*ng/mL at the 3.0 mg/kg dose level. Normalization of AUC0-t by dose (µg/kg) appeared to remove the effect of dose on exposure, and this suggested that exposure may increase linearly with dose. A modest accumulation from week 1 to week 4 was observed with average patient Cmax and AUC0-t accumulation index values of 1.12 and 1.34, respectively. No obvious effect of RBV on the exposure to PEG-IFN-λ was detected. To explore the effect of body weight on exposure, AUC0-t/dose (µg) estimates were compared to the body weight. No trend was detected, and linear regression analysis indicated no apparent effect of weight on exposure.
Although there was no continuous relationship between exposure and change in ALT, very high exposure was observed in patients who demonstrated significant ALT elevations. Among patients dosed QW, six had a PEG-IFN-λ AUC0-t value > 225 h ng/mL; four of these patients (67%) experienced DLT. Conversely, there appeared to be a continuous relationship between PEG-IFN-λ exposure and decreases in HCV RNA, with robust antiviral activity observed at exposures both above and below 225 h*ng/mL (Fig. 4).
Pharmacodynamics.
A rapid rise in ß2M levels was observed after the first dose of PEG-IFN-λ; levels peaked on day 4 and decreased toward the baseline values by day 8. Increases in ß2M were observed at all dose levels, and this confirmed pharmacological activity. A potential relationship between ß2M induction and decreases in HCV RNA was observed. In general, patients who had the greatest HCV RNA decline on day 8 had the strongest induction of ß2M. In addition, minimal or no induction of ß2M was observed in patients with only minimal changes in HCV RNA on day 8, and this suggested that the lack of a virological response in these patients was likely related to an absence of pharmacological activity.
Immunogenicity.
Low-titer antibodies specific to PEG-IFN-λ developed in 3 of 56 patients (5.4%) during the study (all in the treatment-relapse group). Neutralizing activity was observed on day 59 in one of these patients (1.8%); this patient achieved a ≥2-log decrease from the baseline in HCV RNA on days 22 and 29.
Two additional treatment-relapse patients had detectable antibodies to PEG-IFN-λ prior to treatment and throughout the study period; neither had a titer increase during the study. One of these patients had neutralizing antibodies and had very low or unmeasurable PEG-IFN-λ serum levels and no antiviral response throughout the study period. The second patient had preexisting but nonneutralizing antibodies to PEG-IFN-λ and had measurable serum levels of PEG-IFN-λ as well as an antiviral response (a 3.81-log10 decrease on day 29).
DISCUSSION
This study was the first designed to assess the safety, tolerability, and efficacy of PEG-IFN-λ in patients chronically infected with genotype 1 HCV. The results indicate that a broad range of PEG-IFN-λ doses exhibit antiviral activity with limited toxicity when it is administered QW, and this supports the hypothesis that PEG-IFN-λ may be a useful agent in future HCV treatment regimens
SVR, the most definitive measure of antiviral activity, was not evaluated in this study because patients received only 4 weeks of therapy with PEG-IFN-λ with or without RBV. However, relationships between early viral kinetics and long-term response are well established and add clinical relevance to the 4-week antiviral results observed in the current study. Predictive markers of response, including rapid virological response (defined as undetectable HCV RNA at week 4) and early virological response (defined as a >2-log10 decrease in HCV RNA by week 12), have been demonstrated to predict response in treatment-naive patients treated with PEG-IFN-α plus RBV and in treatment-relapse patients as well.17-21 A recent report demonstrated that a ≥2-log10 decrease in HCV RNA by week 4 had a positive predictive value of 52% and a negative predictive value of 94% for predicting SVR in treatment-relapse patients receiving PEG-IFN-α in combination with RBV.19
Parts 1 and 2 of the study included patients who had previously responded to therapy with PEG-IFN-α, and this allowed a close examination of the safety profile in a group of patients who were expected to demonstrate antiviral activity (proof of concept) within a short treatment period. As anticipated, antiviral activity was observed in the majority of treatment-relapse patients, especially in those who received a dose of PEG-IFN-λ ≥ 1.5 µg/kg QW with or without RBV, with 23 of 24 patients (96%) achieving at least a >2-log10 decrease in HCV RNA. Although information on the viral kinetics of the patients' previous responses to IFN-α-based therapies was not collected as part of the study, this magnitude of HCV RNA decrease in the first 4 weeks of therapy indicates clear antiviral activity potentially comparable to that of PEG-IFN-α.
Unambiguous antiviral activity was also observed in the cohort of treatment-naive patients who were all treated with 1.5 µg/kg PEG-IFN-λ QW plus RBV. Six of the seven treatment-naive patients (86%) achieved a >2-log10 decrease in HCV RNA, and two of seven (29%) achieved undetectable HCV RNA; this was an encouraging result despite the small sample size. Historically published rates of >2-log10 decreases in HCV RNA or undetectable HCV RNA after 4 weeks of therapy with PEG-IFN-α plus RBV in treatment-naive patients range from 42% to 67% and from 7.4% to 11.7%, respectively.3, 16, 22
Recent evidence indicates that the viral response to PEG-IFN-α plus RBV may have a genetic basis.23, 24 Single nucleotide polymorphisms upstream from the IL-28B gene on chromosome 19 have been found to be associated with SVR to PEG-IFN-α plus RBV treatment as well as natural clearance of HCV infection.23-27 These links to IL-28B were initially found through genome-wide association studies, so the mechanism of action was not determined. The connection to PEG-IFN-λ is of interest because IL-28B is also a type III IFN known as IFN-λ3, which shares approximately 70% sequence identity with IFN-λ1 and shares the same receptor with IFN-λ1. The genes for IFN-λ1 (IL-29), IFN-λ2 (IL-28A), and IFN-λ3 (IL-28B) are all located in this same region of chromosome 19. It is possible that the IFN-λ family has unique antiviral effects important to the control of HCV infection, and studies to assess the impact of the different polymorphisms on the antiviral response to PEG-IFN-λ plus RBV are being conducted.
Overall, PEG-IFN-λ, given QW for 4 weeks, was safe and was well tolerated by most patients. Minimal constitutional symptoms or hematologic effects were observed with PEG-IFN-λ as a single agent. As expected, the addition of RBV increased the incidence of fatigue and other constitutional symptoms in treatment-relapse patients. Previously untreated patients experienced a low incidence of adverse events, despite combination therapy with RBV, and this suggested a possible experience effect from previous treatment in the treatment-relapse patients. The majority of significant aminotransferase elevations occurred in patients with high PEG-IFN-λ exposure values, which were well above the mean for the individual cohorts. Dose reductions were not allowed in the current study. However, because the aminotransferase elevations were reversible and may be related to high exposure, it may be possible in future studies to manage these effects with dose reductions.
Pharmacokinetic data suggest that the relationship between dose and exposure may be linear and that body weight is not an important determinant of exposure. Future studies will explore fixed microgram doses of PEG-IFN-λ; this is expected to be less complicated for self-administration than weight-based dosing. In addition, the use of a ready-to-use formulation in future studies may also reduce the interpatient variability in PEG-IFN-λ exposure estimates.
Only one patient developed a neutralizing antibody to PEG-IFN-λ during the study. Because the antibody was not observed until day 59, 4 weeks after the last dose of PEG-IFN-λ, no conclusions can be drawn regarding a potential effect on the PEG-IFN-λ serum concentration or antiviral activity. The incidence of neutralizing antibody formation with PEG-IFN-α is approximately 2% to 3%, although direct comparisons between different products may not be valid because the observed incidence of antibody positivity is highly dependent on the sensitivity of the assay.5, 6
These safety and tolerability results observed with the 4-week PEG-IFN-λ treatment compare favorably with the results of published studies of 48-week PEG-IFN-α therapy, in which up to 67% of patients have experienced fatigue, 62% have experienced headache, 56% have experienced myalgia, 48% have experienced rigors, 46% have experienced fever, 43% have experienced nausea, and 40% have experienced insomnia.3, 28 Although direct comparisons with the safety of PEG-IFN-α therapy are not possible because of the 4-week treatment duration in the current study, the incidence of constitutional side effects observed with PEG-IFN-λ therapy appears to be lower. The myelosuppression associated with IFN-α treatment is related to its binding to leukocytes.29 Although adverse hematologic events may appear after 4 weeks of therapy, the absence of IFN-λ binding to leukocytes may explain why such adverse effects have not yet been observed with PEG-IFN-λ therapy.
Key limitations in the current study include the lack of a direct comparison between PEG-IFN-λ and PEG-IFN-α, and this restricts any conclusions regarding the relative effects of one agent with respect to the other. Because the current study encompassed only 4 weeks of dosing, the long-term effects of PEG-IFN-λ could not be determined. The open-label design of the study may have influenced adverse event reporting. Lastly, the study included only patients with genotype 1 HCV infection, and it is not known if these results will translate to patients with other genotypes. Future studies will explore these questions.
The findings from this study offer evidence that PEG-IFN-λ, given QW for 4 weeks, exhibits potent antiviral effects against HCV with the potential for an improved tolerability profile with respect to that traditionally observed for PEG-IFN-α. These results are being tested in larger randomized controlled trials enrolling treatment-naive patients.
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