Public release date: 22-Nov-2011
Contact: Sarah Stamper
sarah.stamper@liv.ac.uk
01-517-943-044
University of Liverpool
The University of Liverpool has launched an iphone app, HEP i-chart, that provides Hepatitis C (HCV) patients with quick and easy access to the latest information about drug interactions.
Hepatitis C was first discovered in the 1980s when it became apparent that there was a new virus (not the already known hepatitis A or B) causing liver damage. Hepatitis C causes inflammation and swelling of the liver. It is estimated that over 170million individuals – representing 3% of the world's population – are chronically infected with the Hepatitis C virus (HCV). Statistically, as many people are infected with HCV as are with HIV.
Since its identification, drug treatment to eradicate the virus has advanced greatly, especially in the last few years. Two new drugs have recently been licensed for treatment of HCV, and there are more drugs in development.
HEP i-chart is based on the website (http://www.hep-druginteractions.org/) developed at the University by Professor David Back and Professor Saye Khoo which provides a comprehensive online guide to the interactions between anti-hepatitis drugs and other drugs. It is a tool that provides
Hepatitis C patients and healthcare professionals with immediate access to up-to-date information on potential drug interactions between HCV drugs, and other drugs that the patient may be prescribed as well as over-the-counter, recreational or herbal medications.
Existing HCV drugs, newly licensed drugs and drugs in development can have interactions with each other and with other drugs which can impact on their effectiveness – sometimes with serious consequences. For this reason, some drug combinations must not be used, whilst others must be given with caution, possibly requiring adjustment or monitoring.
Professor of Pharmacology, David Back, said: "We are delighted to launch with our partners – KnowledgePoint360, MSD and Janssen- this new i-phone application that provides Hepatitis C patients and healthcare professionals with instant and easy access to information about HCV drug interactions which is relevant and reliable and up-to-date. This resource is especially important as new HCV drug treatments are approved and come into use."
Professor Graham Foster, President of the British Association for the Study of the Liver (BASL) said: "This new app, HEP i-chart, is a timely and much-needed resource for HCV patients as the number of new drugs which are available to treat Hepatitis C increases."
Source
November 22, 2011
Organ Transplants and Cancer Risk
November 21, 2011
Organ transplant recipients have a high risk of developing 32 different types of cancer, according to a new study. Future research to understand why may lead to better strategies for preventing cancer among transplant recipients.
In 2010, over 28,000 organ transplantations were performed in the U.S., including 16,899 kidney, 6,291 liver, 2,333 heart and 1,770 lung transplants. Transplant recipients are known to be at a higher risk for developing cancer than the general population. But past studies of cancer risk in transplant recipients focused mainly on those who received kidney transplants. Other studies were too small to accurately estimate risk for all but the most common cancer types.
For a more comprehensive look, a research team led by Dr. Eric A. Engels of NIH's National Cancer Institute (NCI) evaluated medical data from more than 175,000 transplant recipients—about 40% of all organ transplant recipients in the country. Their report appeared in the November 2, 2011, issue of the Journal of the American Medical Association.
The researchers found a twofold overall increased risk of cancer among transplant recipients. They noted elevated risk for 32 different types of cancer, some known to be related to infectious agents (such as anal cancer and Kaposi sarcoma) and others unrelated to infections (such as melanoma and thyroid cancer). The most common cancers among transplant recipients were non-Hodgkin lymphoma (14% of all cancers in transplant recipients), lung cancer (13%), liver cancer (9%) and kidney cancer (7%).
The risk of cancer was affected by the type of transplant. Lung cancer risk, for example, was highest in lung recipients. Smoking-related disease is often the reason for a lung transplant, and lung cancer typically arises in the remaining diseased lung rather than the transplanted one. The risk of liver cancer was elevated only among liver recipients. That might be partly explained by hepatitis B or C infection in the transplanted liver or by the fact that diabetes is common among transplant recipients. The risk of kidney cancer, in contrast, increased for all recipients.
“While transplantation is a life-saving therapy for patients with end-stage organ disease, it also puts recipients at an increased risk for developing cancer, in part because of medications administered to suppress the immune system and prevent rejection of the organ,” Engels says. “The cancer risk among transplant recipients resembles that of people with HIV infection, whose risk is elevated for infection-related cancers due to immunosuppression.”
The researchers now plan to focus on the cancers that occur at higher rates among transplant recipients. They aim to discover how medical conditions and immunosuppressive medications contribute to cancer risk. “In addition, we hope our findings will stimulate other research into the carcinogenic mechanisms associated with organ transplantation,” Engels says.
Source
Liver Cancer Treatment Turns Up the Heat on Chemotherapy
By John Fauber, Reporter, Milwaukee Journal Sentinel/MedPage Today
Published: November 21, 2011
As Mark Vetter lay on the operating table, doctors isolated his liver and began bathing it in a heated, highly toxic poison sent through the organ's blood vessels.
Over the course of an hour, cancer cells in the liver started to die and continued doing so for days.
The operating room at Froedtert Hospital in the Milwaukee area was filled with onlookers who wanted to get a glimpse because the treatment was one that few doctors have witnessed.
"If everything is successful it will kill the remaining cancer cells and it is a healthy liver," a hopeful Vetter said a couple weeks after recovering from the surgery.
For someone like Vetter, who hopes to live for years, there is enough science to offer a glimmer of hope, but also the dark reality that the treatment may only offer another year or so.
The therapy he chose to undergo may have its physiological underpinnings in a theory that has come to be known as the "Lance Armstrong Effect."
The legendary cyclist bounced back from testicular cancer that had metastasized to his lungs and brain, and he went on to win several Tour de France races.
The Armstrong Effect
Why did Armstrong and nearly 70% of other testicular cancer patients survive, even when the disease had metastasized to other parts of the body?
The answer, according to proponents of this theory, lies in anatomy -- the testicles normally are a few degrees cooler than the rest of the body, and when testicular cancer cells spread to other, warmer environments inside the body, they are confronted by a heat wave.
In that stressed state, the theory goes, the cancer cells become more susceptible to treatments such as chemotherapy and radiation.
The combination of heat and chemo may be a promising approach to treating intractable cancers, said Robert Getzenberg, MD, the Johns Hopkins University School of Medicine researcher who coined the term "Lance Armstrong Effect" five years ago in a commentary in the Journal of the American Medical Association.
"We have not had much success with cancer," Getzenberg said. "There are few things that really work. Every drug we come up with, cancer develops a resistance to," Getzenberg said.
Old Idea Finds New Believers
For decades, doctors have known that heat can kill cancer cells. Dating back to the 1960s, small trials of combining heat and chemotherapy were conducted, but the treatment never caught on mainly because of its complexity and a lack of data showing a clear survival benefit, said H. Richard Alexander, MD, associate chairman of clinical research at the University of Maryland Medical Center.
But in the 1990s, Alexander and other researchers began finding benefit in difficult-to-treat cancers that had spread to the liver.
"If (liver perfusion) were just a pill, the FDA would approve it immediately because it is as good as anything else we have tried," he said. "In some patients you see very dramatic results. In some cases, you can make tumors disappear from x-rays."
But tumors can come back. So far, the gold standard of research -- a large, randomized clinical trial -- has yet to be done. So data on the survival benefit remain lacking.
To date, most of the observational research suggests that average survival is extended about a year.
At the University of Pittsburgh Medical Center, about 25 liver perfusion cases are done a year, said cancer surgeon David Bartlett, MD.
Average survival is about two years, he said. About 5% of patients live five years. One man still is alive 12 years after undergoing the treatment, Bartlett said.
Not Too Hot, Not Too Cold
At Froedtert, the doctors use a basic, highly invasive approach:
"We can heat them so much that we can burn them up," Getzenberg said.
The ideal approach, though, which now is being tested with prostate cancer in lab and animal models, involves heating the tumors to 107 degrees, which makes them much more vulnerable to chemotherapy agents, he said. Such nanoparticle and heat cancer therapies remain unproven and likely are a few years down the road
The "If" Factor
From his perspective as a patient undergoing a newly discovered "old" therapeutic approach, the treatment is just one more "if" for Vetter.
If he had not gone in for a routine eye exam two years ago, doctors would not have found the tumor in his left eye and he might be dead -- he's one of about five in one million people a year who develop ocular melanoma, a disease that often metastasizes to the liver.
If he had preferred, he could have traveled hundreds of miles to one of a couple centers in the country that specialize in the unconventional treatment. Instead, he chose to be one of the first such patients to undergo that unconventional treatment at a center in his hometown.
Of course, there is the biggest if: if this treatment works, how long will he live?
At 66, Vetter, a Milwaukee area private labor attorney, is no Lance Armstrong.
He looks trim and fit, hardly like someone who had been battling an often fatal disease for more than two years.
The Process
The treatment Vetter underwent lasted about an hour, "the most tolerable duration," according to T. Clark Gamblin, MD, one of the Froedtert/Medical College of Wisconsin cancer surgeon who operated on Vetter.
The trick is to get the right mix of chemo, heat, and time so to be lethal to cancer cells without causing too much harm to healthy liver cells. While some normal liver cells may die, that's acceptable because the liver has the ability to regenerate tissue.
"You are putting the liver on bypass," said Kiran Turaga, MD, a Froedtert/Medical College cancer surgeon. "It's like the liver is out of the body."
Vetter's surgery was the second such case at the hospital and the latest in a long line of treatments he has tried.
As a veteran of the cancer war, he knows he will be undergoing continual monitoring in the months to come.
He also says he understands there is no way to know how much the treatment will help.
"I have not changed much of anything about the way I live my life," he said in a recent interview from his Milwaukee area home. "My goal is to be sitting in this room in 20 years."
Source
Published: November 21, 2011
As Mark Vetter lay on the operating table, doctors isolated his liver and began bathing it in a heated, highly toxic poison sent through the organ's blood vessels.
Over the course of an hour, cancer cells in the liver started to die and continued doing so for days.
The operating room at Froedtert Hospital in the Milwaukee area was filled with onlookers who wanted to get a glimpse because the treatment was one that few doctors have witnessed.
"If everything is successful it will kill the remaining cancer cells and it is a healthy liver," a hopeful Vetter said a couple weeks after recovering from the surgery.
For someone like Vetter, who hopes to live for years, there is enough science to offer a glimmer of hope, but also the dark reality that the treatment may only offer another year or so.
The therapy he chose to undergo may have its physiological underpinnings in a theory that has come to be known as the "Lance Armstrong Effect."
The legendary cyclist bounced back from testicular cancer that had metastasized to his lungs and brain, and he went on to win several Tour de France races.
The Armstrong Effect
Why did Armstrong and nearly 70% of other testicular cancer patients survive, even when the disease had metastasized to other parts of the body?
The answer, according to proponents of this theory, lies in anatomy -- the testicles normally are a few degrees cooler than the rest of the body, and when testicular cancer cells spread to other, warmer environments inside the body, they are confronted by a heat wave.
In that stressed state, the theory goes, the cancer cells become more susceptible to treatments such as chemotherapy and radiation.
The combination of heat and chemo may be a promising approach to treating intractable cancers, said Robert Getzenberg, MD, the Johns Hopkins University School of Medicine researcher who coined the term "Lance Armstrong Effect" five years ago in a commentary in the Journal of the American Medical Association.
"We have not had much success with cancer," Getzenberg said. "There are few things that really work. Every drug we come up with, cancer develops a resistance to," Getzenberg said.
Old Idea Finds New Believers
For decades, doctors have known that heat can kill cancer cells. Dating back to the 1960s, small trials of combining heat and chemotherapy were conducted, but the treatment never caught on mainly because of its complexity and a lack of data showing a clear survival benefit, said H. Richard Alexander, MD, associate chairman of clinical research at the University of Maryland Medical Center.
But in the 1990s, Alexander and other researchers began finding benefit in difficult-to-treat cancers that had spread to the liver.
"If (liver perfusion) were just a pill, the FDA would approve it immediately because it is as good as anything else we have tried," he said. "In some patients you see very dramatic results. In some cases, you can make tumors disappear from x-rays."
But tumors can come back. So far, the gold standard of research -- a large, randomized clinical trial -- has yet to be done. So data on the survival benefit remain lacking.
To date, most of the observational research suggests that average survival is extended about a year.
At the University of Pittsburgh Medical Center, about 25 liver perfusion cases are done a year, said cancer surgeon David Bartlett, MD.
Average survival is about two years, he said. About 5% of patients live five years. One man still is alive 12 years after undergoing the treatment, Bartlett said.
Not Too Hot, Not Too Cold
At Froedtert, the doctors use a basic, highly invasive approach:
- Wheel the patient to the operating room
- Make a long incision in the abdomen
- Isolate the liver with clips, catheters, and cannulas, and perfuse it with the drug melphalan
- The drug is heated to about 102 degrees and mixed at concentration 20 times stronger than a standard chemotherapy dose
"We can heat them so much that we can burn them up," Getzenberg said.
The ideal approach, though, which now is being tested with prostate cancer in lab and animal models, involves heating the tumors to 107 degrees, which makes them much more vulnerable to chemotherapy agents, he said. Such nanoparticle and heat cancer therapies remain unproven and likely are a few years down the road
The "If" Factor
From his perspective as a patient undergoing a newly discovered "old" therapeutic approach, the treatment is just one more "if" for Vetter.
If he had not gone in for a routine eye exam two years ago, doctors would not have found the tumor in his left eye and he might be dead -- he's one of about five in one million people a year who develop ocular melanoma, a disease that often metastasizes to the liver.
If he had preferred, he could have traveled hundreds of miles to one of a couple centers in the country that specialize in the unconventional treatment. Instead, he chose to be one of the first such patients to undergo that unconventional treatment at a center in his hometown.
Of course, there is the biggest if: if this treatment works, how long will he live?
At 66, Vetter, a Milwaukee area private labor attorney, is no Lance Armstrong.
He looks trim and fit, hardly like someone who had been battling an often fatal disease for more than two years.
The Process
The treatment Vetter underwent lasted about an hour, "the most tolerable duration," according to T. Clark Gamblin, MD, one of the Froedtert/Medical College of Wisconsin cancer surgeon who operated on Vetter.
The trick is to get the right mix of chemo, heat, and time so to be lethal to cancer cells without causing too much harm to healthy liver cells. While some normal liver cells may die, that's acceptable because the liver has the ability to regenerate tissue.
"You are putting the liver on bypass," said Kiran Turaga, MD, a Froedtert/Medical College cancer surgeon. "It's like the liver is out of the body."
Vetter's surgery was the second such case at the hospital and the latest in a long line of treatments he has tried.
As a veteran of the cancer war, he knows he will be undergoing continual monitoring in the months to come.
He also says he understands there is no way to know how much the treatment will help.
"I have not changed much of anything about the way I live my life," he said in a recent interview from his Milwaukee area home. "My goal is to be sitting in this room in 20 years."
Source
New treatments of chronic hepatitis C
Presse Med. 2011 Nov 4. [Epub ahead of print]
Hôpital Cochin et Inserm U1016, Assistance publique-Hôpitaux de Paris, université Paris-Descartes, unité d'hépatologie, 75014 Paris, France.
Abstract
The current treatment of chronic hepatitis C since several years, the association of pegylated interferon and ribavirine, allows to obtain a virological eradication in 55% of patients, all genotypes and 45% of those infected with the genotype 1, the most prevalent. The cure, defined by an undetectable viremia 24 weeks after the discontinuation of treatment is associated to a improvement of the prognosis of the patients with a decrease of mortality and morbidity. The development of news antiviral C molecules, efficient against the genotype 1, two protease inhibitors, boceprevir or telaprevir (which approval has been recently obtained), in association with pegylated interferon and ribavirine, allows to obtain a viral eradication in 70 to 75% of cases, with a reduction of treatment duration to 24 weeks in half of patients. This evolution will modify the therapeutic indications, the therapeutic schemas, the virologic follow-up, the risk factors of sustained virological reponse, the tolerance with the appearance of new adverse effects.
Copyright © 2011. Published by Elsevier Masson SAS.
Copyright © 2011. Published by Elsevier Masson SAS.
November 20, 2011
No HIV Disease Progression in Transplant Recipients
Sandra Yin
November 18, 2011 (Bethesda, Maryland) — Now that people infected with HIV are living longer, physicians are seeing a growing number who need kidney or liver transplants because of comorbid conditions. But what happens when you take patients in an immunosuppressed population, give them new organs, and further immunosuppress them with drugs to prevent rejection of those organs?
HIV does not progress in HIV-positive transplant recipients, according to findings from a study titled "Opportunistic Infections and Neoplasms Following Liver and Kidney Transplantation in the HIV Infected Recipient," which was presented at the 13th International Conference on Malignancies in AIDS and Other Acquired Immunodeficiencies (ICMAOI) here at the National Institutes of Health (NIH).
But there is a much higher incidence of organ rejection, indicating a dysregulated immune system rather than an absence of immunity, investigators said.
"The take-home message is that HIV is not the issue," Peter Stock, MD, PhD, professor of surgery at the University of California at San Francisco. He was the principal investigator of a multicenter trial in patients with HIV who received liver or kidney transplants.
"It's the comorbidities that are the issue. In other words, we did not see progression of HIV in any of the transplantations. Nor did we see an increase in the incidence of AIDS-related malignancies."
The aim of the trial was to evaluate the effect of HIV infection on graft function and survival, study the effect of transplantation and post-transplant immunosuppression on HIV progression and markers of immune function and activity, and describe the pharmacokinetic interactions between immunosuppressive agents and antiretroviral agents.
The NIH-funded trial involved 150 kidney and 125 liver transplants at 18 centers across the United States, with 3- to 4-year follow up. Patients selected for the study had CD4+ T-cell counts greater than 200 cells/mm3 for kidney recipients and greater than 100 cells/mm3 for liver recipients. For kidney patients, the HIV viral load had to be undetectable while the patients were receiving a stable antiviral regimen. A detectable HIV viral load was permitted in liver recipients as long as the HIV providers said that the virus could be suppressed after transplantation. Researchers excluded patients with opportunistic infections that could not be treated, such as cryptosporidiosis and visceral Kaposi's sarcoma. Post-treatment management included prophylaxis against opportunistic infections, immunosuppression, management of rejection, and antiretroviral therapy.
Of 150 kidney transplant recipients, 20% were co-infected with hepatitis C virus (HCV) at baseline. The median follow-up was 3.6 years. One in 4 patients had a history of opportunistic infections before transplantation.
For the 150 kidney transplant recipients, researchers reported that HIV generally remained suppressed and CD4 counts remained relatively stable. When they used antithymocyte globulin, patients' CD4 counts were wiped out for a year and they still saw minimal opportunistic infections in the year it took for the CD4 counts to come back. The investigators did see a higher incidence of serious bacterial infections, about 2-fold greater, in the patients whose CD4+ counts were deleted. Both patient and graft survival were similar to that in the general population at 1 and 3 years.
The main problem, Dr. Stock said, was a high incidence of organ rejection, 2- to 3-fold higher than what they saw in HIV-negative patients. Research is underway to explore the mechanism behind the high rate of rejection. "But it is real," he said. "It clarifies to me that this is not the absence of an immune system, it is the presence of a very dysregulated immune system."
Among 125 liver transplant recipients, 69% at baseline were co-infected with HCV, 36% had hepatocellular carcinoma, and 12% had a history of opportunistic infections before transplantation. Median duration of follow-up was 4 years.
Compared with patients mono-infected with hepatitis B virus (HBV), HIV-positive liver transplant recipients co-infected with HBV did just as well with their transplants 5 years out. "I think this is the proof that HIV is not the problem," said Dr. Stock. "It's the co-pathogens that are the problem after transplantation. We do a pretty good job of controlling HIV."
HCV was a different story, he said. The 3-year survival rate for the HCV-HIV co-infected group was 64%, compared with 75% for the group with HCV infection only.
Not surprisingly, many centers are balking at transplantations for co-infected patients with HCV, but not those with HBV, because the low survival rate is affecting center-specific results, Dr. Stock said. Those rates could endanger Medicare funding and scare third-party payer referrals away.
Graft survival in co-infected patients at 3 years was 59%, compared with 67% in the mono-infected controls.
The incidence of rejection in the HIV-HCV co-infected patients was 2-fold higher, and 50% of those rejection episodes happened early on.
Treating those rejections is problematic because rejection becomes an independent predictor of graft loss and severe HCV recurrence, Dr. Stock said. Control over the virus and the co-pathogen is lost when these patients are immunosuppressed. "That begs the question of what we're doing to all the viruses that may be associated with cancer," he observed.
"I think the striking thing about the cancer risk in those patients, which is what Dr. Stock was presenting, is that it's not a lot higher than what he observed," Eric Engels, MD, MPH, senior investigator at the National Cancer Institute's Division of Cancer Epidemiology and Genetics, told Medscape Medical News.
There certainly are some cancers, but no more than you would probably expect in a transplant population that did not have HIV infection, Dr. Engels said.
13th International Conference on Malignancies in AIDS and Other Acquired Immunodeficiencies (ICMAOI); Abstract #P6. Presented November 8, 2011.
Source
November 18, 2011 (Bethesda, Maryland) — Now that people infected with HIV are living longer, physicians are seeing a growing number who need kidney or liver transplants because of comorbid conditions. But what happens when you take patients in an immunosuppressed population, give them new organs, and further immunosuppress them with drugs to prevent rejection of those organs?
HIV does not progress in HIV-positive transplant recipients, according to findings from a study titled "Opportunistic Infections and Neoplasms Following Liver and Kidney Transplantation in the HIV Infected Recipient," which was presented at the 13th International Conference on Malignancies in AIDS and Other Acquired Immunodeficiencies (ICMAOI) here at the National Institutes of Health (NIH).
But there is a much higher incidence of organ rejection, indicating a dysregulated immune system rather than an absence of immunity, investigators said.
"The take-home message is that HIV is not the issue," Peter Stock, MD, PhD, professor of surgery at the University of California at San Francisco. He was the principal investigator of a multicenter trial in patients with HIV who received liver or kidney transplants.
"It's the comorbidities that are the issue. In other words, we did not see progression of HIV in any of the transplantations. Nor did we see an increase in the incidence of AIDS-related malignancies."
The aim of the trial was to evaluate the effect of HIV infection on graft function and survival, study the effect of transplantation and post-transplant immunosuppression on HIV progression and markers of immune function and activity, and describe the pharmacokinetic interactions between immunosuppressive agents and antiretroviral agents.
The NIH-funded trial involved 150 kidney and 125 liver transplants at 18 centers across the United States, with 3- to 4-year follow up. Patients selected for the study had CD4+ T-cell counts greater than 200 cells/mm3 for kidney recipients and greater than 100 cells/mm3 for liver recipients. For kidney patients, the HIV viral load had to be undetectable while the patients were receiving a stable antiviral regimen. A detectable HIV viral load was permitted in liver recipients as long as the HIV providers said that the virus could be suppressed after transplantation. Researchers excluded patients with opportunistic infections that could not be treated, such as cryptosporidiosis and visceral Kaposi's sarcoma. Post-treatment management included prophylaxis against opportunistic infections, immunosuppression, management of rejection, and antiretroviral therapy.
Of 150 kidney transplant recipients, 20% were co-infected with hepatitis C virus (HCV) at baseline. The median follow-up was 3.6 years. One in 4 patients had a history of opportunistic infections before transplantation.
For the 150 kidney transplant recipients, researchers reported that HIV generally remained suppressed and CD4 counts remained relatively stable. When they used antithymocyte globulin, patients' CD4 counts were wiped out for a year and they still saw minimal opportunistic infections in the year it took for the CD4 counts to come back. The investigators did see a higher incidence of serious bacterial infections, about 2-fold greater, in the patients whose CD4+ counts were deleted. Both patient and graft survival were similar to that in the general population at 1 and 3 years.
The main problem, Dr. Stock said, was a high incidence of organ rejection, 2- to 3-fold higher than what they saw in HIV-negative patients. Research is underway to explore the mechanism behind the high rate of rejection. "But it is real," he said. "It clarifies to me that this is not the absence of an immune system, it is the presence of a very dysregulated immune system."
Among 125 liver transplant recipients, 69% at baseline were co-infected with HCV, 36% had hepatocellular carcinoma, and 12% had a history of opportunistic infections before transplantation. Median duration of follow-up was 4 years.
Compared with patients mono-infected with hepatitis B virus (HBV), HIV-positive liver transplant recipients co-infected with HBV did just as well with their transplants 5 years out. "I think this is the proof that HIV is not the problem," said Dr. Stock. "It's the co-pathogens that are the problem after transplantation. We do a pretty good job of controlling HIV."
HCV was a different story, he said. The 3-year survival rate for the HCV-HIV co-infected group was 64%, compared with 75% for the group with HCV infection only.
Not surprisingly, many centers are balking at transplantations for co-infected patients with HCV, but not those with HBV, because the low survival rate is affecting center-specific results, Dr. Stock said. Those rates could endanger Medicare funding and scare third-party payer referrals away.
Graft survival in co-infected patients at 3 years was 59%, compared with 67% in the mono-infected controls.
The incidence of rejection in the HIV-HCV co-infected patients was 2-fold higher, and 50% of those rejection episodes happened early on.
Treating those rejections is problematic because rejection becomes an independent predictor of graft loss and severe HCV recurrence, Dr. Stock said. Control over the virus and the co-pathogen is lost when these patients are immunosuppressed. "That begs the question of what we're doing to all the viruses that may be associated with cancer," he observed.
"I think the striking thing about the cancer risk in those patients, which is what Dr. Stock was presenting, is that it's not a lot higher than what he observed," Eric Engels, MD, MPH, senior investigator at the National Cancer Institute's Division of Cancer Epidemiology and Genetics, told Medscape Medical News.
There certainly are some cancers, but no more than you would probably expect in a transplant population that did not have HIV infection, Dr. Engels said.
13th International Conference on Malignancies in AIDS and Other Acquired Immunodeficiencies (ICMAOI); Abstract #P6. Presented November 8, 2011.
Source
November 18, 2011
AASLD: HCV Testing by Birth Cohort Cost-Effective
Published: November 04, 2011
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner
SAN FRANCISCO -- Birth-cohort screening for hepatitis C virus (HCV) infection proved highly cost-effective, even when adjusted for universal treatment with direct-acting antiviral therapy, according to a study reported here.
Universal HCV testing in people born from 1945 to 1965 would detect 800,000 new cases of HCV infection and prevent 82,000 deaths at a cost of $15,700 per quality-adjusted life year (QALY) gained.
Assuming treatment with pegylated interferon and ribavirin would prevent an estimated 121,000 deaths at a cost of $35,700 per QALY, still well within the generally accepted range for cost effectiveness.
The findings were reported simultaneously here at the American Association for the Study of Liver Diseases meeting and online in Annals of Internal Medicine.
"Without new case identification strategies, the adverse consequences of chronic HCV infection are forecasted to result in an increasing public health burden over the next two decades," David P. Rein, PhD, of the National Opinion Research Center at the University of Chicago, and co-authors wrote in conclusion.
"Birth-cohort screening appears to be a reasonable strategy to identify asymptomatic cases of HCV," they added.
More than four million Americans have antibodies to HCV, which leads to chronic infection in about 75% of cases. HCV infection occurs most often in adults born between 1945 and 1965, most of whom acquire infection 20 to 40 years before diagnosis, the authors wrote in their introduction.
Estimates of HCV-related mortality ranged between 7,000 and 13,000 deaths in 2005. Without changes in the current approach to case identification, the number of HCV deaths will increase to 35,000 a year by 2030, the authors continued.
Clinical trials of pegylated interferon and ribavirin have demonstrated efficacy in 46% of patients infected with HCV genotype 1 (which accounts for 70% of infected white patients and 90% of African Americans in the U.S.) and 81% of patients infected with genotype 2 or 3.
The CDC recommends antibody testing for individuals with a history of behaviors, exposures, or health indicators associated with HCV infection (such as intravenous drug use and hemodialysis). Even so, as many as 50% of HCV-infected individuals may be unaware of their status, the authors wrote.
Expanding screening recommendations to the birth cohort covering 1945 to 1965 offers one potential means to increase detection and treatment of HCV infection. Such a strategy would increase healthcare costs, but whether the additional cost would offset potential benefits of expanded screening is unclear.
To address the issue, Rein and colleagues performed an analysis based on data derived from the National Health and Nutrition Examination Survey, census data, Medicare reimbursement information, and published sources.
The analytic model included the estimated cost of HCV testing in the 67 million Americans born from 1945 through 1965 who had at least one visit to a primary care provider in 2006. The authors also calculated the lifetime cost of treating the estimated 2.4 million patients with HCV-positive test results, illness-related lost productivity, increased loss of QALYs, and other relevant factors.
As compared with the current approach to identification of HCV infection, birth-cohort screening would identify 808,580 additional cases of HCV infection at a cost of $2,874 per case. Treatment of the additional cases would result in an additional 348,800 QALYs gained at a total cost of $5.5 billion, resulting in incremental cost-effectiveness ratio (ICER) of $15,700 per QALY.
Expanding the definition of treatment to consist of a direct-acting antiviral, pegylated interferon, and ribavirin results in an additional 532,200 QALYs gained at a cost of $19 billion and an ICER of $35,700 per QALY saved.
Sensitivity analysis yielded a stable ICER that was most sensitive to discounting and QALY losses assigned to disease states, the authors wrote.
Acknowledging limitations of their analysis, Rein and colleagues cited a scarcity of empirical data on screening and treatment with a direct-acting antiviral in real-world clinical settings. Nonetheless, they concluded, "birth-cohort screening for HCV in primary-care settings was highly cost-effective."
The study was supported by the CDC.
The authors had no relevant disclosures.
Primary source: Annals of Internal Medicine
Source reference:
Rein DB, et al "The cost-effectiveness of birth cohort hepatitis C antibody screening in U.S. primary care settings" Ann Intern Med 2011; 155(9): epub.
Source
Adverse CNS Effects of HCV Treatment Discourage Adherence
Neil Canavan
November 18, 2011 (San Francisco, California) — Patients infected with hepatitis C virus (HCV) can experience a marked decline in neuropsychological cognitive function in the first 14 weeks of combination pegylated interferon and ribavirin therapy. This poses a potential treat to treatment adherence, said clinical psychologist Jeffrey J. Weiss, PhD, MS, from Mount Sinai School of Medicine in New York City, here at The Liver Meeting 2011: American Association for the Study of Liver Diseases 62nd Annual Meeting.
These data are from a large prospective study looking at early treatment discontinuation and the onset of neuropsychiatric symptomatology in HCV monoinfected and HCV/HIV coinfected treatment-naïve patients receiving combination pegylated interferon/ribavirin therapy, Dr. Weiss explained.
"A lot of work has focused on depression, and not to the decrements in cognitive function," said Dr. Weiss. A host of neuropsychiatric symptoms should be considered when initiating a new treatment.
"In this era of direct-acting antivirals, when we're asking patients to take medications 3 times a day (every 6 to 9 hours)..., we need to be aware that, just at baseline, 40% to 50% of patients...[have] substantial deficits in cognitive functioning."
This investigation established the degree of neurocognitive decline during the first 12 and 48 weeks of treatment. Both HCV-infected and HCV/HIV-coinfected patients were evaluated. Neuropsychological instruments were used to explore which domains of cognitive functioning are most affected by combination pegylated interferon/ribavirin treatment, and whether being coinfected with HIV adds to the decrements in cognitive functioning.
There were no significant differences at baseline between the HCV-infected and HCV/HIV-coinfected cohorts for age, sex distribution, ethnicity, HCV RNA viral load, HCV genotype, or stage of liver disease. There were also no differences between the 2 groups at baseline for neuropsychological scores. However, although the same percentage of patients in the HCV and HCV/HIV cohorts reported depression, HCV patients had significantly worse depression scores.
After treatment, global neuropsychological function declined significantly in HCV patients during the first 24 weeks of HCV treatment. Domains with the greatest declines were memory, executive function, and motor function. "The HCV monoinfected group also had a greater decline in neuropsychological function than the coinfected group in the first 12 weeks," said Dr. Weiss. "This is probably due to more depression among HCV patients at baseline."
How a patient's declining neuropsychological function affects their behavior is key, and can depend on clinical history, Dr. Weiss explained. "Patients who have a history of cognitive dysfunction might respond less to the onset of new symptoms. Patients with a significant pathology who are already well engaged in psychiatric treatment tend to do quite well on [antiretroviral] treatment because they are familiar with the symptoms and are being well managed." Those who are high functioning at baseline will have more trouble; to be successfully managed, the healthcare provider must be aware of the potential for central nervous system (CNS)-related treatment nonadherence.
CNS and the Hepatologist
Raymond T. Chung, MD, vice chief of the gastrointestinal unit and medical director of the liver transplant program at Massachusetts General Hospital in Boston, agrees that the hepatologist must be part psychiatrist. "We field these patients rather then pass them off since there can often be overlap with true advanced hepatic disease and hepatic encephalopathy."
He is mindful of the potential impact of HCV medications. "It has been a modest issue with both HCV/HIV and HCV alone." Symptoms are often called "brain fog," Dr. Chung explained. "This fog does get in the way, in high-functioning individuals, of their ability to carry out intricate calculative functions and memory at work, for instance." It would not be surprising for such a patient to become frustrated and consider forgoing medication, he observed.
Dr. Chung considers the issue manageable if it is proactively addressed. However, like many clinicians at the meeting, he's looking more toward preventing than managing adverse effects by eliminating pegylated interferon from standard HCV treatment.
Dr. Weiss reports being a consultant for Vertex Pharmaceuticals and Kadmon Pharmaceuticals. Dr. Chung has disclosed no relevant financial relationships.
The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting. Abstract 972. November 6, 2011.
Source
November 18, 2011 (San Francisco, California) — Patients infected with hepatitis C virus (HCV) can experience a marked decline in neuropsychological cognitive function in the first 14 weeks of combination pegylated interferon and ribavirin therapy. This poses a potential treat to treatment adherence, said clinical psychologist Jeffrey J. Weiss, PhD, MS, from Mount Sinai School of Medicine in New York City, here at The Liver Meeting 2011: American Association for the Study of Liver Diseases 62nd Annual Meeting.
These data are from a large prospective study looking at early treatment discontinuation and the onset of neuropsychiatric symptomatology in HCV monoinfected and HCV/HIV coinfected treatment-naïve patients receiving combination pegylated interferon/ribavirin therapy, Dr. Weiss explained.
"A lot of work has focused on depression, and not to the decrements in cognitive function," said Dr. Weiss. A host of neuropsychiatric symptoms should be considered when initiating a new treatment.
"In this era of direct-acting antivirals, when we're asking patients to take medications 3 times a day (every 6 to 9 hours)..., we need to be aware that, just at baseline, 40% to 50% of patients...[have] substantial deficits in cognitive functioning."
This investigation established the degree of neurocognitive decline during the first 12 and 48 weeks of treatment. Both HCV-infected and HCV/HIV-coinfected patients were evaluated. Neuropsychological instruments were used to explore which domains of cognitive functioning are most affected by combination pegylated interferon/ribavirin treatment, and whether being coinfected with HIV adds to the decrements in cognitive functioning.
There were no significant differences at baseline between the HCV-infected and HCV/HIV-coinfected cohorts for age, sex distribution, ethnicity, HCV RNA viral load, HCV genotype, or stage of liver disease. There were also no differences between the 2 groups at baseline for neuropsychological scores. However, although the same percentage of patients in the HCV and HCV/HIV cohorts reported depression, HCV patients had significantly worse depression scores.
After treatment, global neuropsychological function declined significantly in HCV patients during the first 24 weeks of HCV treatment. Domains with the greatest declines were memory, executive function, and motor function. "The HCV monoinfected group also had a greater decline in neuropsychological function than the coinfected group in the first 12 weeks," said Dr. Weiss. "This is probably due to more depression among HCV patients at baseline."
How a patient's declining neuropsychological function affects their behavior is key, and can depend on clinical history, Dr. Weiss explained. "Patients who have a history of cognitive dysfunction might respond less to the onset of new symptoms. Patients with a significant pathology who are already well engaged in psychiatric treatment tend to do quite well on [antiretroviral] treatment because they are familiar with the symptoms and are being well managed." Those who are high functioning at baseline will have more trouble; to be successfully managed, the healthcare provider must be aware of the potential for central nervous system (CNS)-related treatment nonadherence.
CNS and the Hepatologist
Raymond T. Chung, MD, vice chief of the gastrointestinal unit and medical director of the liver transplant program at Massachusetts General Hospital in Boston, agrees that the hepatologist must be part psychiatrist. "We field these patients rather then pass them off since there can often be overlap with true advanced hepatic disease and hepatic encephalopathy."
He is mindful of the potential impact of HCV medications. "It has been a modest issue with both HCV/HIV and HCV alone." Symptoms are often called "brain fog," Dr. Chung explained. "This fog does get in the way, in high-functioning individuals, of their ability to carry out intricate calculative functions and memory at work, for instance." It would not be surprising for such a patient to become frustrated and consider forgoing medication, he observed.
Dr. Chung considers the issue manageable if it is proactively addressed. However, like many clinicians at the meeting, he's looking more toward preventing than managing adverse effects by eliminating pegylated interferon from standard HCV treatment.
Dr. Weiss reports being a consultant for Vertex Pharmaceuticals and Kadmon Pharmaceuticals. Dr. Chung has disclosed no relevant financial relationships.
The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting. Abstract 972. November 6, 2011.
Source
Two New Drugs Poised to Replace Interferon in HCV Treatment
Neil Canavan
November 18, 2011 (San Francisco, California) — Two new compounds — a protease inhibitor and a polymerase inhibitor — have the potential to replace pegylated interferon in standard treatment regimens for hepatitis C virus (HCV), according to late-breaking data reported here at The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting.
In an interim analysis of the open-label phase 2b SOUND-C2 study, investigators looked at the novel protease inhibitor BI 201335 (BI35, Boehringer Ingelheim) and the novel polymerase inhibitor BI 207127 (BI27, Boehringer Ingelheim).
The analysis involved 362 treatment-naïve patients with HCV genotype 1. In the cohort, 52% were male, 98% were white, 85% had an HCV RNA viral load of at least 800,000 IU/mL at baseline, 39% had HCV genotype 1a, 10% showed evidence of compensated cirrhosis, and 26% carried the interleukin (IL)28B polymorphism C/C genotype.
The 5 treatment groups, which all received BI35 120 mg once daily, were:
• BI27 600 mg 3 times a day plus ribavirin for 16 weeks, for 28 weeks, or for 40 weeks (thrice-daily groups)
• BI27 600 mg twice daily plus ribavirin for 28 weeks (twice-daily group)
• BI27 600 mg 3 times daily without ribavirin for 28 weeks (no-ribavirin group).
"Having 2 investigational compounds in 1 trial is a bit unusual," noted Federico Mensa, MD, from the division of clinical research in virology at Boehringer Ingelheim Pharmaceuticals in Ridgefield, Connecticut.
"The idea is to take interferon out of the regimen equation. That treatment is associated with so many adverse events that many patients don't even want to start treatment," Dr. Mensa noted. It's thought that the combination of 2 of the so-called direct-acting antiviral agents will also prevent the emergence of resistance prior to sustained virologic response, he added.
The interim analysis was performed after all patients completed 12 weeks of treatment. Data for the 238 patients in the 16-week and 28-week thrice-daily groups were combined, since those patients received the same treatment for the first 12 weeks.
Results at week 4 show that response to antiviral treatment (HCV RNA viral load below the lower limit of quantification) ranged from 88% for the thrice-daily groups to 72% for the no-ribavirin group.
At week 12, responses ranged from 76% for the twice-daily group to 57% for the no-ribavirin group.
At weeks 4 and 8, virologic failure occurred in 3.4%, 1.3%, and 4.3% of patients in the thrice-daily, twice-daily, and no-ribavirin groups, respectively.
Virologic breakthrough at 12 weeks occurred in 13.4%, 20.5%, and 32.6% of patients in the twice-daily, thrice-daily, and no-ribavirin groups, respectively.
Patients infected with HCV genotype 1a had a lower response rate than others in the study, particularly those in the no-ribavirin group. The lowest rate of response was for IL28B non-C/C patients in the no-ribavirin group (22%); it was 100% in patients with the C/C genotype in the no-ribavirin group. Excellent response was seen in genotype 1b patients, regardless of IL28B status.
"Viral response rates at 12 weeks of up to 76% were comparable to complete early virologic responses achieved with first-generation protease inhibitors plus pegylated interferon," said Dr. Mensa.
How do low response rates observed for patients with HCV genotype 1a, IL28B non-C/C stack up? "This is an important question. Right now my understanding is that we have not seen that data published — the response rates for genotype 1a patients with the unfavorable C/C IL28b variant are not available, to my knowledge, for boceprevir or telaprivir. So it is hard to make a comparison," said Dr. Mensa.
There were some early discontinuations recorded for reasons other than virologic failure, including adverse events and patients lost to follow-up — 17% in the thrice-daily groups, 6% in the twice-daily group, and 13% in the no-ribavirin group. The most common adverse events were mild to moderate gastrointestinal or skin events.
Discussions are ongoing regarding the treatment protocol for a planned phase 3 study using these agents.
What Took So Long?
"Clearly, the protease inhibitors have shot ahead of the nonnukes [polymerase inhibitors], especially because the structural chemistry was understood earlier," said David R. Nelson, MD, associate dean for clinical research in the division of gastroenterology, hepatology, and nutrition at the University of Florida College of Medicine in Gainesville. "Protease inhibitors have also been much more potent than the typical nonnukes. There were some in development prior to protease inhibitors, but the potency of these drugs early on is what limited clinical trial results."
Dr. Nelson is the lead investigator of the ZENITH trial, in which the polymerase inhibitor VX-222 (Vertex Pharmaceuticals) is being combined with the recently approved protease inhibitor telaprevir in a population of treatment-naïve patients infected with HCV genotype 1.
The ZENITH trial is looking at the efficacy and tolerability of VX-222, telaprevir, and ribavirin with and without pegylated interferon. Response rates for the pegylated-interferon-free group will be reported at the 2012 meeting of the European Association of the Study of the Liver.
Dr. Mensa reports being an employee of Boehringer Ingelheim. Dr. Nelson reports being a consultant for Bayer HealthCare, Biolex, and Roche; and receiving grants and research support from Abbott, Anadys Pharmaceuticals, Bayer HealthCare, BMS, Gilead Sciences, Human Genome Sciences, Merck, Novartis, Roche, and Vertex Pharmaceuticals.
The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting. Late-breaking abstract 15, presented November 7, 2011. Abstract 14, presented November 9, 2011.
Source
November 18, 2011 (San Francisco, California) — Two new compounds — a protease inhibitor and a polymerase inhibitor — have the potential to replace pegylated interferon in standard treatment regimens for hepatitis C virus (HCV), according to late-breaking data reported here at The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting.
In an interim analysis of the open-label phase 2b SOUND-C2 study, investigators looked at the novel protease inhibitor BI 201335 (BI35, Boehringer Ingelheim) and the novel polymerase inhibitor BI 207127 (BI27, Boehringer Ingelheim).
The analysis involved 362 treatment-naïve patients with HCV genotype 1. In the cohort, 52% were male, 98% were white, 85% had an HCV RNA viral load of at least 800,000 IU/mL at baseline, 39% had HCV genotype 1a, 10% showed evidence of compensated cirrhosis, and 26% carried the interleukin (IL)28B polymorphism C/C genotype.
The 5 treatment groups, which all received BI35 120 mg once daily, were:
• BI27 600 mg 3 times a day plus ribavirin for 16 weeks, for 28 weeks, or for 40 weeks (thrice-daily groups)
• BI27 600 mg twice daily plus ribavirin for 28 weeks (twice-daily group)
• BI27 600 mg 3 times daily without ribavirin for 28 weeks (no-ribavirin group).
"Having 2 investigational compounds in 1 trial is a bit unusual," noted Federico Mensa, MD, from the division of clinical research in virology at Boehringer Ingelheim Pharmaceuticals in Ridgefield, Connecticut.
"The idea is to take interferon out of the regimen equation. That treatment is associated with so many adverse events that many patients don't even want to start treatment," Dr. Mensa noted. It's thought that the combination of 2 of the so-called direct-acting antiviral agents will also prevent the emergence of resistance prior to sustained virologic response, he added.
The interim analysis was performed after all patients completed 12 weeks of treatment. Data for the 238 patients in the 16-week and 28-week thrice-daily groups were combined, since those patients received the same treatment for the first 12 weeks.
Results at week 4 show that response to antiviral treatment (HCV RNA viral load below the lower limit of quantification) ranged from 88% for the thrice-daily groups to 72% for the no-ribavirin group.
At week 12, responses ranged from 76% for the twice-daily group to 57% for the no-ribavirin group.
At weeks 4 and 8, virologic failure occurred in 3.4%, 1.3%, and 4.3% of patients in the thrice-daily, twice-daily, and no-ribavirin groups, respectively.
Virologic breakthrough at 12 weeks occurred in 13.4%, 20.5%, and 32.6% of patients in the twice-daily, thrice-daily, and no-ribavirin groups, respectively.
Patients infected with HCV genotype 1a had a lower response rate than others in the study, particularly those in the no-ribavirin group. The lowest rate of response was for IL28B non-C/C patients in the no-ribavirin group (22%); it was 100% in patients with the C/C genotype in the no-ribavirin group. Excellent response was seen in genotype 1b patients, regardless of IL28B status.
"Viral response rates at 12 weeks of up to 76% were comparable to complete early virologic responses achieved with first-generation protease inhibitors plus pegylated interferon," said Dr. Mensa.
How do low response rates observed for patients with HCV genotype 1a, IL28B non-C/C stack up? "This is an important question. Right now my understanding is that we have not seen that data published — the response rates for genotype 1a patients with the unfavorable C/C IL28b variant are not available, to my knowledge, for boceprevir or telaprivir. So it is hard to make a comparison," said Dr. Mensa.
There were some early discontinuations recorded for reasons other than virologic failure, including adverse events and patients lost to follow-up — 17% in the thrice-daily groups, 6% in the twice-daily group, and 13% in the no-ribavirin group. The most common adverse events were mild to moderate gastrointestinal or skin events.
Discussions are ongoing regarding the treatment protocol for a planned phase 3 study using these agents.
What Took So Long?
"Clearly, the protease inhibitors have shot ahead of the nonnukes [polymerase inhibitors], especially because the structural chemistry was understood earlier," said David R. Nelson, MD, associate dean for clinical research in the division of gastroenterology, hepatology, and nutrition at the University of Florida College of Medicine in Gainesville. "Protease inhibitors have also been much more potent than the typical nonnukes. There were some in development prior to protease inhibitors, but the potency of these drugs early on is what limited clinical trial results."
Dr. Nelson is the lead investigator of the ZENITH trial, in which the polymerase inhibitor VX-222 (Vertex Pharmaceuticals) is being combined with the recently approved protease inhibitor telaprevir in a population of treatment-naïve patients infected with HCV genotype 1.
The ZENITH trial is looking at the efficacy and tolerability of VX-222, telaprevir, and ribavirin with and without pegylated interferon. Response rates for the pegylated-interferon-free group will be reported at the 2012 meeting of the European Association of the Study of the Liver.
Dr. Mensa reports being an employee of Boehringer Ingelheim. Dr. Nelson reports being a consultant for Bayer HealthCare, Biolex, and Roche; and receiving grants and research support from Abbott, Anadys Pharmaceuticals, Bayer HealthCare, BMS, Gilead Sciences, Human Genome Sciences, Merck, Novartis, Roche, and Vertex Pharmaceuticals.
The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting. Late-breaking abstract 15, presented November 7, 2011. Abstract 14, presented November 9, 2011.
Source
Colonoscopy and Hepatitis C
Level of α-Fetoprotein Predicts Mortality Among Patients With Hepatitis C–Related Hepatocellular Carcinoma
Clinical Gastroenterology and Hepatology
Volume 9, Issue 11 , Pages 989-994, November 2011
Gia L. Tyson, Zhigang Duan, Jennifer R. Kramer, Jessica A. Davila, Peter A. Richardson, Hashem B. El–Serag
published online 05 August 2011
Abstract
Background & Aims
Hepatocellular carcinoma (HCC) can result from hepatitis C virus (HCV)-related liver disease and is the fastest-growing cause of cancer-related death in the United States. α-fetoprotein (AFP) has been used as a prognostic factor for HCC, but the value of AFP as a prognostic factor for HCV-related HCC in the United States is unknown. We investigated whether higher levels of AFP at the time of diagnosis are associated with increased mortality of patients with HCV-related HCC.
Methods
In a retrospective study, we collected data from a cohort of HCV-infected veterans, identifying incident HCC cases from October 1, 1998, to January 1, 2007 (n = 1480 patients). The mean serum levels of AFP, obtained within 60 days before to 30 days after HCC diagnosis, were determined for 1064 patients and categorized as less than 10 ng/mL (18%), 10 to less than 100 ng/mL (30%), 100 to less than 1000 ng/mL (22%), or 1000 ng/mL or more (29%). Cox proportional hazard models were used to associate serum levels of AFP with mortality, adjusting for demographic features, clinical factors, and treatment.
Results
The median survival times were significantly lower among patients with higher levels of AFP: 709 days for patients with less than 10 ng/mL, 422 days for patients with 10 to less than 100 ng/mL, 208 days for patients with 100 to less than 1000 ng/mL, and 68 days for patients with 1000 ng/mL or more. In the multivariate analysis, increased levels of AFP (10 to <100, 100 to <1000, and ≥1000) were associated significantly with increased mortality, compared with a serum AFP level of less than 10; hazard ratios were 1.50, 2.23, and 4.35, respectively.
Conclusions
Serum AFP level at the time of diagnosis with HCV-related HCC is an independent predictor of mortality.
Source
Volume 9, Issue 11 , Pages 989-994, November 2011
Gia L. Tyson, Zhigang Duan, Jennifer R. Kramer, Jessica A. Davila, Peter A. Richardson, Hashem B. El–Serag
published online 05 August 2011
Abstract
Background & Aims
Hepatocellular carcinoma (HCC) can result from hepatitis C virus (HCV)-related liver disease and is the fastest-growing cause of cancer-related death in the United States. α-fetoprotein (AFP) has been used as a prognostic factor for HCC, but the value of AFP as a prognostic factor for HCV-related HCC in the United States is unknown. We investigated whether higher levels of AFP at the time of diagnosis are associated with increased mortality of patients with HCV-related HCC.
Methods
In a retrospective study, we collected data from a cohort of HCV-infected veterans, identifying incident HCC cases from October 1, 1998, to January 1, 2007 (n = 1480 patients). The mean serum levels of AFP, obtained within 60 days before to 30 days after HCC diagnosis, were determined for 1064 patients and categorized as less than 10 ng/mL (18%), 10 to less than 100 ng/mL (30%), 100 to less than 1000 ng/mL (22%), or 1000 ng/mL or more (29%). Cox proportional hazard models were used to associate serum levels of AFP with mortality, adjusting for demographic features, clinical factors, and treatment.
Results
The median survival times were significantly lower among patients with higher levels of AFP: 709 days for patients with less than 10 ng/mL, 422 days for patients with 10 to less than 100 ng/mL, 208 days for patients with 100 to less than 1000 ng/mL, and 68 days for patients with 1000 ng/mL or more. In the multivariate analysis, increased levels of AFP (10 to <100, 100 to <1000, and ≥1000) were associated significantly with increased mortality, compared with a serum AFP level of less than 10; hazard ratios were 1.50, 2.23, and 4.35, respectively.
Conclusions
Serum AFP level at the time of diagnosis with HCV-related HCC is an independent predictor of mortality.
Source
November 17, 2011
Protons, Electrons, and Hepatitis C
Written by Jessica Wapner
PLoS Blogs
Posted: November 9, 2011
Well, technically that title should be PROTON, ELECTRON, and Hepatitis C, the first two words being the names of two recent studies of PSI-7977, a potential new drug for treating hepatitis C virus (HCV).
The Latest Findings
There’s a lot to talk about with PSI-7977—mainly in light of study results presented a few days ago at the 62nd Annual Meeting of the Association for the Study of Liver Diseases (AASLD) in San Francisco. So let’s get the elephant in the room out of the way before we go any further: I do not know what POSITRON and ELECTRON stand for. Nor do I know what FISSION, PROTON, and ATOMIC stand for—but more on that later. All I can tell you is that at some point in the history of drug development, pharmaceutical companies and/or clinical trial cooperative groups decided that acronyms were necessary or advantageous for some reason, paving the way for many a BLT, BOLERO and COMFORT for years to come.
PSI-7977 is kind of exciting. In the PROTON study, this drug, a nucleotide analog, was combined with the then-standard of care, pegylated interferon plus ribavirin. (Since PROTON was done, telaprevir and boceprevir were approved, changing the standard of care.) In PROTON, 96% of patients had a sustained virologic response (SVR), which is the measure of cure for HCV. Now, to balance this, is a wonderful moment of parsing the data: 96% is impressive, no doubt, but it has to be mentioned that the total number of patients in that study was 25, with 24 patients being actually evaluable. It was an early-phase study, so that small number of patients is not unusual, but most reports about the latest PSI-7977 results are highlighting that initial 96%, and it’s hard to find the actual N of the study. Here is a PDF of the full report of the PROTON study.
After PROTON delivered its encouraging results, Pharmasset, the maker of PSI-7977, launched ELECTRON, a phase II study in which a number of patients were given the experimental drug plus ribavirin. And that is the key: 10 of the enrollees received NO pegylated interferon. And guess what: the combination worked. All 10 of those HCV patients had an SVR.
Now, a couple of things to explain. First, these were patients with genotype 2 or 3 HCV. The reason why these genotypes were selected is because they tend to be highly responsive to interferon. Wait – so, why were those the people who were not given interferon? Well, the logic was that if PSI-7977 plus ribavirin didn’t work, those patients could be more easily rescued with a course of pegylated interferon + ribavirin than HCV patients with, say, genotype 1, the most difficult to treat variety of the disease. As it turned out, that rescue therapy wasn’t needed, but still, the logic is interesting when it comes to understanding drug trials.
Another important point is why eliminating interferon from treatment could be useful. There are two reasons. First, some patients respond to interferon and others do not. As it turns out, variations in the IL28B gene are behind that likelihood (or lack thereof), a discovery that has its own fascinating story. (Here’s a link to an article I wrote about it for Science last year.) David Goldstein, of Duke University, was instrumental in this finding, as was David Thomas, director of the Division of Infectious Diseases at Johns Hopkins School of Medicine, a man whose work with HCV, along with hepatitis B and other illnesses, extends from the genetic aspects to the public health injustices surrounding screening and care.
The second point about interferon is that it’s not for everyone, even those who do respond physically. The drug causes harsh side effects, including mood disorders, to the point where some patients, such as those who are clinically depressed at the time of their diagnosis, may not be candidates for treatment, even if they have the IL28B variant that indicates they’d likely respond to the drug. In short, many researchers and drug developers have been working on finding a way to treat HCV without pegylated interferon. The ELECTRON study is the first (as far as I know) to do it.
In the ELECTRON study, alongside those 10 patients given PSI-7977 + ribavirin were three other groups of patients, each of which was given a different schedule of PSI-7977 + ribavirin + pegylated interferon. All of the patients responded well. The outcomes among the patients not given pegylated interferon were the same as for those given that drug. The difference was that patients in the three-drug groups experienced at least one side effect more often (any of the following: headache, fatigue, depression, insomnia, anxiety, irritability, muscle soreness, upper respiratory tract infections), as well as a greater occurrence of moderate-to-severe drops in neutrophils, a type of white blood cell.
Several new treatment arms have been added to the ELECTRON study, including one in which patients will be given PSI-7977 alone. All of the patients are still genotype 2/3 only.
Another word about the genotype selection. Telaprevir (Incivek) and bocepevir (Victrelis) were both approved for genotype 1 HCV. These drugs are highly effective, and while they won’t cure all patients, they will cure many. So it may be that the drug maker behind PSI-7977 is focusing on a different genotype for marketing purposes. That being said, the phase III clinical trial program will include three studies, one of which will focus on genotype-1 patients. The other two soon-to-be-launched studies (the aforementioned FISSION and POSITRON) will evaluate PSI-7977 + ribavirin in more than 700 patients with genotype 2/3 HCV, according to a recent statement from Pharmasset. And we mustn’t forget the other ongoing study, ATOMIC, a phase IIb study in which 300 patients with chronic HCV genotype 1 are being given the three-drug combo for either 12 or 24 weeks, and 25 patients with genotype 4, 5, 6 or an indeterminate genotype will receive the same medications for 24 weeks.
Other New Drugs for Hepatitis C
If HCV were a party, this would be the point at which the room starts getting a touch crowded; not so much that you have to leave, but definitely to the point where there are no seats left. For although PSI-7977 has got the makers of telaprevir a little concerned about its future earnings, several other compounds, many of which may also work without pegylated interferon, are currently being studied. These include:
• Second-generation protease inhibitors (telaprevir and boceprevir are protease inhibitors) such as TMC435, danoprevir, GS 9256, BMS 791325, ACH-1625, MK-7009, and BI 201335
• Inhibitors of nonstructural protein 5A, which is involved with viral replication. BMS 790052 is one such compound currently being evaluated
• R7128, another nucleoside polymerase inhibitor (same class as PSI-7977)
• Nonnucleoside polymerase inhibitors (which, for the technically minded among you, seem to exert their effect by “allosteric inhibition of the NS5B HCV polymerase,” according to Ira Jacobson, commenting in Gastroenterology & Hepatology, in October 2010.)
• Cyclophilin antagonists, drugs that target the host cell rather than the virus. Cyclophilin is a protein that the virus uses in the replication of RNA. One of the reasons why this approach could gain traction is because it eliminates concern about the virus becoming resistant to treatment, a feature that warrants having as many treatment options as possible, meaning that it’s probably good that this party is getting crowded.
• Alternatives to pegylated interferon are also being investigated. For example, albumin interferon alfa-2b and pegylated interferon lambda are two candidates. Loteron is an interferon alpha product that could work, and consensus interferon, which is nonpegylated, was already approved for patients who don’t respond to pegylated interferon plus ribavirin.
HCV and the History of the Human Race
On another, related note, we all come across certain topics where we feel like the trajectory of the story somehow encapsulates all there is to understand about human life, or some other big picture for which this smaller story serves as a microcosm. For me, HCV is one of those stories. This current chapter is not only illuminating so much about the best of modern drug development, but also reveals many of the problems still not being adequately addressed, like screening and prevention (HCV is primarily transferred through dirty drug needles), and the fact that many HCV patients are still not treated until late in the disease, one of the reasons why being a passing of the buck going on at the level of insurance. There is also the question (warning: idealist alert) of whether we will ever come to the day when people won’t feel the need to inject recreational drugs, dirty needle or not, and eliminating, or at least severely shrinking, HCV as a concern once and for all.
But then there is a whole trace of human history—steps and missteps—in the story of HCV. The geographic distribution of genotypes is a starting point for a rich and harrowing look at how viruses move across the world. For example, one of the ways that hepatitis was spread through Egypt was through a campaign against schistosomiasis along the Nile delta in the 1960s. (Here is one interesting PDF on that.) It was a well-intentioned and needed public health measure but the needles weren’t sterilized and so as people were treated for the parasite, village by village, the virus made its way around. Egypt currently has the highest rates of HCV in the world. Anti-malaria campaigns in Cameroon had a similar impact.
Also fascinating is the fact that the spread of the virus can be traced across slave trade routes from Africa to Europe. And, as Oliver Pybus, an evolutionary biologist at Oxford University, points out, that fact brings up another central mystery about HCV, which is that the virus has been around for thousands of years, but the most common modes of transmission that we know of are connected to relatively modern inventions (blood transfusions and needles to inject drugs). “What is clear is that this endemic transmission was occurring across the whole of Sub-Saharan Africa and Asia and it doesn’t seem right that it would be maintained by very culturally-defined and location-specific routes of transmission,” Pybus once told me. In other words, as he explained, practices like scarification and tattooing could account for some, but not all, of the spread of HCV in that time and place. Making his insights even more fascinating is the fact that Pybus has managed to use genome sequencing and computer programs to trace the phylogenetic tree of HCV that extends over thousands of years. (Pybus was the WHO’s point person on tracking the origin of swine flu a few years back because of the software and methods he’s invented.)
Then there is the question of how HCV got into humans in the first place. Columbia University virologist Ian Lipkin recently shed some fascinating light on this question when he found a genetic homolog of HCV in dogs. Here’s a tiny bit from me on that (scroll to bottom), and a lot more about it from Carl Zimmer.
You see? There is a whole trace of history inside the story of HCV. With all of the issues that tend to get our dander up when it comes to drug development (and those exist with HCV, too), here is one that piques our fascination and curiosity.
There is one more looming question. When it comes to the increasing number of HCV medications: why now? We know that pharmaceutical companies are businesses, so obviously there is money to be made in creating new drugs for HCV. Has there been some recent dawning realization about this? Are drug makers for some reason now guaranteed a solid return on the investment, whereas they weren’t some years back? Or is it more due to the science and advances in HCV research that have led to so many new targets to investigate?
Clearly, there is at least one more chapter waiting to be written in this compelling story, and I’m sure many more beyond that.
Source
PLoS Blogs
Posted: November 9, 2011
Well, technically that title should be PROTON, ELECTRON, and Hepatitis C, the first two words being the names of two recent studies of PSI-7977, a potential new drug for treating hepatitis C virus (HCV).
The Latest Findings
There’s a lot to talk about with PSI-7977—mainly in light of study results presented a few days ago at the 62nd Annual Meeting of the Association for the Study of Liver Diseases (AASLD) in San Francisco. So let’s get the elephant in the room out of the way before we go any further: I do not know what POSITRON and ELECTRON stand for. Nor do I know what FISSION, PROTON, and ATOMIC stand for—but more on that later. All I can tell you is that at some point in the history of drug development, pharmaceutical companies and/or clinical trial cooperative groups decided that acronyms were necessary or advantageous for some reason, paving the way for many a BLT, BOLERO and COMFORT for years to come.
PSI-7977 is kind of exciting. In the PROTON study, this drug, a nucleotide analog, was combined with the then-standard of care, pegylated interferon plus ribavirin. (Since PROTON was done, telaprevir and boceprevir were approved, changing the standard of care.) In PROTON, 96% of patients had a sustained virologic response (SVR), which is the measure of cure for HCV. Now, to balance this, is a wonderful moment of parsing the data: 96% is impressive, no doubt, but it has to be mentioned that the total number of patients in that study was 25, with 24 patients being actually evaluable. It was an early-phase study, so that small number of patients is not unusual, but most reports about the latest PSI-7977 results are highlighting that initial 96%, and it’s hard to find the actual N of the study. Here is a PDF of the full report of the PROTON study.
After PROTON delivered its encouraging results, Pharmasset, the maker of PSI-7977, launched ELECTRON, a phase II study in which a number of patients were given the experimental drug plus ribavirin. And that is the key: 10 of the enrollees received NO pegylated interferon. And guess what: the combination worked. All 10 of those HCV patients had an SVR.
Now, a couple of things to explain. First, these were patients with genotype 2 or 3 HCV. The reason why these genotypes were selected is because they tend to be highly responsive to interferon. Wait – so, why were those the people who were not given interferon? Well, the logic was that if PSI-7977 plus ribavirin didn’t work, those patients could be more easily rescued with a course of pegylated interferon + ribavirin than HCV patients with, say, genotype 1, the most difficult to treat variety of the disease. As it turned out, that rescue therapy wasn’t needed, but still, the logic is interesting when it comes to understanding drug trials.
Another important point is why eliminating interferon from treatment could be useful. There are two reasons. First, some patients respond to interferon and others do not. As it turns out, variations in the IL28B gene are behind that likelihood (or lack thereof), a discovery that has its own fascinating story. (Here’s a link to an article I wrote about it for Science last year.) David Goldstein, of Duke University, was instrumental in this finding, as was David Thomas, director of the Division of Infectious Diseases at Johns Hopkins School of Medicine, a man whose work with HCV, along with hepatitis B and other illnesses, extends from the genetic aspects to the public health injustices surrounding screening and care.
The second point about interferon is that it’s not for everyone, even those who do respond physically. The drug causes harsh side effects, including mood disorders, to the point where some patients, such as those who are clinically depressed at the time of their diagnosis, may not be candidates for treatment, even if they have the IL28B variant that indicates they’d likely respond to the drug. In short, many researchers and drug developers have been working on finding a way to treat HCV without pegylated interferon. The ELECTRON study is the first (as far as I know) to do it.
In the ELECTRON study, alongside those 10 patients given PSI-7977 + ribavirin were three other groups of patients, each of which was given a different schedule of PSI-7977 + ribavirin + pegylated interferon. All of the patients responded well. The outcomes among the patients not given pegylated interferon were the same as for those given that drug. The difference was that patients in the three-drug groups experienced at least one side effect more often (any of the following: headache, fatigue, depression, insomnia, anxiety, irritability, muscle soreness, upper respiratory tract infections), as well as a greater occurrence of moderate-to-severe drops in neutrophils, a type of white blood cell.
Several new treatment arms have been added to the ELECTRON study, including one in which patients will be given PSI-7977 alone. All of the patients are still genotype 2/3 only.
Another word about the genotype selection. Telaprevir (Incivek) and bocepevir (Victrelis) were both approved for genotype 1 HCV. These drugs are highly effective, and while they won’t cure all patients, they will cure many. So it may be that the drug maker behind PSI-7977 is focusing on a different genotype for marketing purposes. That being said, the phase III clinical trial program will include three studies, one of which will focus on genotype-1 patients. The other two soon-to-be-launched studies (the aforementioned FISSION and POSITRON) will evaluate PSI-7977 + ribavirin in more than 700 patients with genotype 2/3 HCV, according to a recent statement from Pharmasset. And we mustn’t forget the other ongoing study, ATOMIC, a phase IIb study in which 300 patients with chronic HCV genotype 1 are being given the three-drug combo for either 12 or 24 weeks, and 25 patients with genotype 4, 5, 6 or an indeterminate genotype will receive the same medications for 24 weeks.
Other New Drugs for Hepatitis C
If HCV were a party, this would be the point at which the room starts getting a touch crowded; not so much that you have to leave, but definitely to the point where there are no seats left. For although PSI-7977 has got the makers of telaprevir a little concerned about its future earnings, several other compounds, many of which may also work without pegylated interferon, are currently being studied. These include:
• Second-generation protease inhibitors (telaprevir and boceprevir are protease inhibitors) such as TMC435, danoprevir, GS 9256, BMS 791325, ACH-1625, MK-7009, and BI 201335
• Inhibitors of nonstructural protein 5A, which is involved with viral replication. BMS 790052 is one such compound currently being evaluated
• R7128, another nucleoside polymerase inhibitor (same class as PSI-7977)
• Nonnucleoside polymerase inhibitors (which, for the technically minded among you, seem to exert their effect by “allosteric inhibition of the NS5B HCV polymerase,” according to Ira Jacobson, commenting in Gastroenterology & Hepatology, in October 2010.)
• Cyclophilin antagonists, drugs that target the host cell rather than the virus. Cyclophilin is a protein that the virus uses in the replication of RNA. One of the reasons why this approach could gain traction is because it eliminates concern about the virus becoming resistant to treatment, a feature that warrants having as many treatment options as possible, meaning that it’s probably good that this party is getting crowded.
• Alternatives to pegylated interferon are also being investigated. For example, albumin interferon alfa-2b and pegylated interferon lambda are two candidates. Loteron is an interferon alpha product that could work, and consensus interferon, which is nonpegylated, was already approved for patients who don’t respond to pegylated interferon plus ribavirin.
HCV and the History of the Human Race
On another, related note, we all come across certain topics where we feel like the trajectory of the story somehow encapsulates all there is to understand about human life, or some other big picture for which this smaller story serves as a microcosm. For me, HCV is one of those stories. This current chapter is not only illuminating so much about the best of modern drug development, but also reveals many of the problems still not being adequately addressed, like screening and prevention (HCV is primarily transferred through dirty drug needles), and the fact that many HCV patients are still not treated until late in the disease, one of the reasons why being a passing of the buck going on at the level of insurance. There is also the question (warning: idealist alert) of whether we will ever come to the day when people won’t feel the need to inject recreational drugs, dirty needle or not, and eliminating, or at least severely shrinking, HCV as a concern once and for all.
But then there is a whole trace of human history—steps and missteps—in the story of HCV. The geographic distribution of genotypes is a starting point for a rich and harrowing look at how viruses move across the world. For example, one of the ways that hepatitis was spread through Egypt was through a campaign against schistosomiasis along the Nile delta in the 1960s. (Here is one interesting PDF on that.) It was a well-intentioned and needed public health measure but the needles weren’t sterilized and so as people were treated for the parasite, village by village, the virus made its way around. Egypt currently has the highest rates of HCV in the world. Anti-malaria campaigns in Cameroon had a similar impact.
Also fascinating is the fact that the spread of the virus can be traced across slave trade routes from Africa to Europe. And, as Oliver Pybus, an evolutionary biologist at Oxford University, points out, that fact brings up another central mystery about HCV, which is that the virus has been around for thousands of years, but the most common modes of transmission that we know of are connected to relatively modern inventions (blood transfusions and needles to inject drugs). “What is clear is that this endemic transmission was occurring across the whole of Sub-Saharan Africa and Asia and it doesn’t seem right that it would be maintained by very culturally-defined and location-specific routes of transmission,” Pybus once told me. In other words, as he explained, practices like scarification and tattooing could account for some, but not all, of the spread of HCV in that time and place. Making his insights even more fascinating is the fact that Pybus has managed to use genome sequencing and computer programs to trace the phylogenetic tree of HCV that extends over thousands of years. (Pybus was the WHO’s point person on tracking the origin of swine flu a few years back because of the software and methods he’s invented.)
Then there is the question of how HCV got into humans in the first place. Columbia University virologist Ian Lipkin recently shed some fascinating light on this question when he found a genetic homolog of HCV in dogs. Here’s a tiny bit from me on that (scroll to bottom), and a lot more about it from Carl Zimmer.
You see? There is a whole trace of history inside the story of HCV. With all of the issues that tend to get our dander up when it comes to drug development (and those exist with HCV, too), here is one that piques our fascination and curiosity.
There is one more looming question. When it comes to the increasing number of HCV medications: why now? We know that pharmaceutical companies are businesses, so obviously there is money to be made in creating new drugs for HCV. Has there been some recent dawning realization about this? Are drug makers for some reason now guaranteed a solid return on the investment, whereas they weren’t some years back? Or is it more due to the science and advances in HCV research that have led to so many new targets to investigate?
Clearly, there is at least one more chapter waiting to be written in this compelling story, and I’m sure many more beyond that.
Source
HBV, HCV Reactivation During Chemotherapy of Concern
Neil Canavan
November 10, 2011 (San Francisco, California) — Two separate studies, performed at the University of Texas M.D. Anderson Cancer Center in Houston, demonstrate the potentially life-threatening impact of reactivation of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection in patients undergoing immunosuppressive chemotherapy.
The data, presented here at The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting, suggest that greater surveillance for HBV and safer hematologic-sparing treatments for HCV are required.
In the first study, lead investigator Jessica P. Hwang, MD, MPH, and colleagues looked at HBV reactivation during cancer treatment using a retrospective dataset from her institution. "This is a topic that is gaining momentum in public health, oncology, as well as hepatology landscapes," she explained. However, because of the lack of large population-based studies, the current prevalence of HBV reactivation in patients undergoing cancer treatment is unclear. "Our goals were to determine the prevalence and predictors of HBV screening and reactivation in a comprehensive cancer center."
What is known is that HBV reactivation can occur at anytime during chemotherapy or after chemotherapy, during the recovery phase of the immune system's reconstitution. "This can lead to poor outcomes, hepatic flares, liver failure, and death," Dr. Hwang said. "It's important to identify these patients accurately so that effective oral antiviral therapy can be initiated."
The study by Dr. Hwang and colleagues explored 2 issues: the existence of inconsistent guidelines for screening cancer patients for HBV, and the lack of adherence to the guidelines that are in place.
The 3 entities that have addressed HBV and cancer are the Centers for Disease Control and Prevention (CDC), the AASLD, and the Association of Clinical Oncology (ASCO).
On screening and treatment, the CDC and AASLD recommendations are in agreement: All patients with cancer who are about to undergo immunosuppressive therapy should be tested for HBV and screened for hepatitis B surface antigen (HBsAg), hepatitis B core antigen (anti-HBc), and antibodies against HBsAg (anti-HBs). If there is a positive test result, HBV prophylaxis should be initiated.
Recommendations from ASCO are less comprehensive: Only those about to undergo "highly" immunosuppressive regimens (i.e., stem cell transplants or treatment with rituximab) and patients "at risk" for HBV should be tested, and screening should only be for HBsAg and anti-HBc (recommended treatment is the same).
"Although there is agreement on the importance of antiviral prophylaxis, ASCO does not advocate the use of all 3 screening tests," Dr. Hwang noted. Furthermore, the ASCO guidelines require that oncologists be aware of the risk factors for HBV infection, and that they take the time to actually perform HBV screening. The discrepancies in recommendations led Dr. Hwang's team to examine current practices at the M.D. Anderson Cancer Center.
The retrospective chart review gathered data on screening, positive tests, and HBV reactivation for all chemotherapy-naïve cancer patients seen at the M.D. Anderson over a 4-year period. Evidence of viral reactivation was defined as an alanine aminotransferase (ALT) level of at least 100 U/L plus total bilirubin of at least 2.5 mg/dL; detectable HBV levels when HBV was previously undetectable; or HBV DNA of at least 100,000 copies/mL.
The screening period was 2 months before the first or second round of chemotherapy. Both solid tumor and hematologic malignancies were considered. Risk factors for HBV prior to screening included International Classification of Diseases, Ninth Revision (ICD-9) codes for HCV, HIV, liver disease, and hepatitis.
Approximately 71,000 charts were reviewed. Of the 10,729 patients receiving potentially immunosuppressive chemotherapy, Dr. Hwang and colleagues found that only 1787 patients (17%) were screened for HBV. Tests used were HBsAg (1665 patients); HBsAg and anti-HBC (87 patients); and anti-HBc (35 patients). "If we just look at the patients with HBV risk factors, only 1 of 5 patients were screened," Dr. Hwang reported.
Of those screened, 34 patients were found to have HBV reactivation. Fourteen of the 34 were found to have chronic HBV infection, and anti-HBc was detected in 20 patients. Of the total reactivation cohort, 23 patients had hematologic cancers, 11 had solid tumors, and 10 had been treated with rituximab.
Predictors of those chosen for screening were being male, having HBV risk factors, having a hematologic malignancy, and the use of rituximab. Predictors of HBV reactivation were being male, being Asian or black, and having HBV risk factors. "Interestingly, Asian and black race did not predict screening, yet they were more often testing positive," said Dr. Hwang.
Most striking was the lack of use of HBV therapy after a positive test. Of the 34 patients, 9 received prophylaxis (2 later died), 11 received treatment after HBV reactivation (8 died), and 14 received no treatment (10 later died).
"It does not appear that we are following the CDC and AASLD recommendations," Dr. Hwang pointed out, adding that M.D. Anderson is not even adhering to ASCO recommendations.
"Preventable reactivation does occur, is occurring, and prophylaxis has been shown to dramatically reduce mortality in cancer patients with HBV," she explained.
HCV Reactivation
A study from the same institution looked at HCV reactivation in patients who had undergone treatment with rituximab and gemcitabine. In this retrospective chart review, investigators looked at the records of 308 HCV-infected patients treated at M.D. Anderson over a 1-year period. HCV exacerbation was defined as a greater than 3-fold increase in ALT in the absence of hepatotoxic drugs, systemic coinfection, recent blood transfusions, and tumor infiltration of the liver.
"We found that 11% of patients who received this chemotherapy developed reactivation of HCV," reported coinvestigator Harrys Torres, MD, assistant professor of infectious diseases at M.D. Anderson. "Interestingly, none of these patients died with liver failure, which is different than with HBV reactivation."
What concerns Dr. Torres is that HCV reactivation necessitates discontinuation of chemotherapy. "We have to stop chemo in 50% of cases," he said. "It seems that HCV reactivation does not compromise the patient from the biologic standpoint, but from the oncologic standpoint, with treatment interruptions," it does.
Treating HCV concurrently with the administration of chemotherapy is not an option. "Current HCV agents are associated with anemia and neutropenia, and these patients already have some sort of hematologic toxicity with the chemotherapy," Dr. Torres said. "In the near future, we're hoping to see new drugs that can be given orally once a day that would allow chemotherapy to continue."
Dr. Hwang reports receiving grant funding from Bristol-Myers Squibb. Dr. Torres reports consulting for Merck, Astellas, and Vertex.
The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting: Abstracts 172 and1732. Presented November 7, 2011.
Source
November 10, 2011 (San Francisco, California) — Two separate studies, performed at the University of Texas M.D. Anderson Cancer Center in Houston, demonstrate the potentially life-threatening impact of reactivation of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection in patients undergoing immunosuppressive chemotherapy.
The data, presented here at The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting, suggest that greater surveillance for HBV and safer hematologic-sparing treatments for HCV are required.
In the first study, lead investigator Jessica P. Hwang, MD, MPH, and colleagues looked at HBV reactivation during cancer treatment using a retrospective dataset from her institution. "This is a topic that is gaining momentum in public health, oncology, as well as hepatology landscapes," she explained. However, because of the lack of large population-based studies, the current prevalence of HBV reactivation in patients undergoing cancer treatment is unclear. "Our goals were to determine the prevalence and predictors of HBV screening and reactivation in a comprehensive cancer center."
What is known is that HBV reactivation can occur at anytime during chemotherapy or after chemotherapy, during the recovery phase of the immune system's reconstitution. "This can lead to poor outcomes, hepatic flares, liver failure, and death," Dr. Hwang said. "It's important to identify these patients accurately so that effective oral antiviral therapy can be initiated."
The study by Dr. Hwang and colleagues explored 2 issues: the existence of inconsistent guidelines for screening cancer patients for HBV, and the lack of adherence to the guidelines that are in place.
The 3 entities that have addressed HBV and cancer are the Centers for Disease Control and Prevention (CDC), the AASLD, and the Association of Clinical Oncology (ASCO).
On screening and treatment, the CDC and AASLD recommendations are in agreement: All patients with cancer who are about to undergo immunosuppressive therapy should be tested for HBV and screened for hepatitis B surface antigen (HBsAg), hepatitis B core antigen (anti-HBc), and antibodies against HBsAg (anti-HBs). If there is a positive test result, HBV prophylaxis should be initiated.
Recommendations from ASCO are less comprehensive: Only those about to undergo "highly" immunosuppressive regimens (i.e., stem cell transplants or treatment with rituximab) and patients "at risk" for HBV should be tested, and screening should only be for HBsAg and anti-HBc (recommended treatment is the same).
"Although there is agreement on the importance of antiviral prophylaxis, ASCO does not advocate the use of all 3 screening tests," Dr. Hwang noted. Furthermore, the ASCO guidelines require that oncologists be aware of the risk factors for HBV infection, and that they take the time to actually perform HBV screening. The discrepancies in recommendations led Dr. Hwang's team to examine current practices at the M.D. Anderson Cancer Center.
The retrospective chart review gathered data on screening, positive tests, and HBV reactivation for all chemotherapy-naïve cancer patients seen at the M.D. Anderson over a 4-year period. Evidence of viral reactivation was defined as an alanine aminotransferase (ALT) level of at least 100 U/L plus total bilirubin of at least 2.5 mg/dL; detectable HBV levels when HBV was previously undetectable; or HBV DNA of at least 100,000 copies/mL.
The screening period was 2 months before the first or second round of chemotherapy. Both solid tumor and hematologic malignancies were considered. Risk factors for HBV prior to screening included International Classification of Diseases, Ninth Revision (ICD-9) codes for HCV, HIV, liver disease, and hepatitis.
Approximately 71,000 charts were reviewed. Of the 10,729 patients receiving potentially immunosuppressive chemotherapy, Dr. Hwang and colleagues found that only 1787 patients (17%) were screened for HBV. Tests used were HBsAg (1665 patients); HBsAg and anti-HBC (87 patients); and anti-HBc (35 patients). "If we just look at the patients with HBV risk factors, only 1 of 5 patients were screened," Dr. Hwang reported.
Of those screened, 34 patients were found to have HBV reactivation. Fourteen of the 34 were found to have chronic HBV infection, and anti-HBc was detected in 20 patients. Of the total reactivation cohort, 23 patients had hematologic cancers, 11 had solid tumors, and 10 had been treated with rituximab.
Predictors of those chosen for screening were being male, having HBV risk factors, having a hematologic malignancy, and the use of rituximab. Predictors of HBV reactivation were being male, being Asian or black, and having HBV risk factors. "Interestingly, Asian and black race did not predict screening, yet they were more often testing positive," said Dr. Hwang.
Most striking was the lack of use of HBV therapy after a positive test. Of the 34 patients, 9 received prophylaxis (2 later died), 11 received treatment after HBV reactivation (8 died), and 14 received no treatment (10 later died).
"It does not appear that we are following the CDC and AASLD recommendations," Dr. Hwang pointed out, adding that M.D. Anderson is not even adhering to ASCO recommendations.
"Preventable reactivation does occur, is occurring, and prophylaxis has been shown to dramatically reduce mortality in cancer patients with HBV," she explained.
HCV Reactivation
A study from the same institution looked at HCV reactivation in patients who had undergone treatment with rituximab and gemcitabine. In this retrospective chart review, investigators looked at the records of 308 HCV-infected patients treated at M.D. Anderson over a 1-year period. HCV exacerbation was defined as a greater than 3-fold increase in ALT in the absence of hepatotoxic drugs, systemic coinfection, recent blood transfusions, and tumor infiltration of the liver.
"We found that 11% of patients who received this chemotherapy developed reactivation of HCV," reported coinvestigator Harrys Torres, MD, assistant professor of infectious diseases at M.D. Anderson. "Interestingly, none of these patients died with liver failure, which is different than with HBV reactivation."
What concerns Dr. Torres is that HCV reactivation necessitates discontinuation of chemotherapy. "We have to stop chemo in 50% of cases," he said. "It seems that HCV reactivation does not compromise the patient from the biologic standpoint, but from the oncologic standpoint, with treatment interruptions," it does.
Treating HCV concurrently with the administration of chemotherapy is not an option. "Current HCV agents are associated with anemia and neutropenia, and these patients already have some sort of hematologic toxicity with the chemotherapy," Dr. Torres said. "In the near future, we're hoping to see new drugs that can be given orally once a day that would allow chemotherapy to continue."
Dr. Hwang reports receiving grant funding from Bristol-Myers Squibb. Dr. Torres reports consulting for Merck, Astellas, and Vertex.
The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting: Abstracts 172 and1732. Presented November 7, 2011.
Source
Liver Cancer: Increasing Incidence, But Greater Therapeutic Options
By: Christopher Siegel, MD, PhD, FACS
Saturday, November 12, 2011
Although hepatocellular carcinoma (HCC) does not garner the type of publicity breast cancer and colon cancer receive, it clearly remains a major cause of cancer mortality.
In the United States, the incidence of liver cancer remains the fifth and ninth leading cause of cancer deaths in men and women with an estimated 13,260 male and 6,330 female deaths in 2011. In contrast to the incidences of colon, lung and breast cancer, which are decreasing, the incidence of liver cancer is increasing.1
Studies (Davila et al, Gastroenterology, 2004) indicate this is in part due to the large number of people infected with viral hepatitis. Because of the latency between viral infection, cirrhosis, and the development of cancer, it has been projected that the number of hepatitis C related liver cancer cases will continue to rise and potentially double over the next 10-20 years (reviewed by El-Serag, Hepatology 2002).
The American Association for the Advancement of Liver Disease (AASLD) has developed recommendations for screening populations at risk. For chronic hepatitis B carriers, the guidelines recommend screening Asian males forty years of age or older, Asian females 50 years of age or older, all hepatitis B carriers with cirrhosis, all hepatitis B carriers with a family history of HCC and African hepatitis B carriers older than 20. Screening should also be offered to patients with cirrhosis related to hepatitis C, alcohol, hemochromatosis, and primary biliary cirrhosis.
Because patients who develop hepatocellular cancer often have cirrhosis as well, treatment algorithms and tumor staging systems have been developed to try to incorporate the degree of hepatic dysfunction in the recommendations for treatment.
For example, the treatment recommendation for a patient with a small tumor but with advanced cirrhosis may be different than a patient with the same size tumor but much better liver function and reserve. Multiple staging systems have been described to try to determine the best way to segregate patients to the appropriate treatment algorithm. One current commonly used algorithm is the Barcelona Clinic Liver Cancer (BCLC) staging classification. This staging system, Fig 1, takes into account underlying liver function as represented by the patient’s Child-Pugh-Turcotte score, as well as, tumor size, vascular involvement, the presence of extrahepatic disease and the patient’s performance status.
Multiple tools have been added to the armamentarium for the treatment of hepatocellular cancers. These can be separated into three categories: surgical, medical and radiological. Surgical options include resection, ablation and transplantation.
In a patient with HCC and no underlying cirrhosis, the goal should be resection if possible. In a study by Llovet et al. (Hepatology 1999), excellent five year survival rates were reported (74%) for patients with a normal bilirubin and no portal hypertension who were treated with resection. Arii et al. (Hepatology 2000) reported similar survival rates for 1,318 patients who underwent resection for the treatment of small (< 2 cm) hepatocellular cancers.
Most patients with hepatocellular cancers and early stage tumors are not candidates for resection based on poor underlying liver function and inadequate liver reserve. Based on a publication by Mazzaferro et al. (NEJM 1996) the United Network for Organ Sharing, UNOS, currently gives special consideration to patients who have a liver cancer that is less than 5 cm in size or have three or fewer tumors, no individual tumor larger than 3 cm. These criteria have become known as the Milan criteria. Patients that satisfy these requirements can be placed on the transplant list and are awarded enough points that they can often be transplanted relatively quickly. In Ohio they often can be transplanted within 3-6 months. Transplant recipients who met Milan criteria were found to have a 75% four year survival.
Ablation may be a possible treatment for patients with small tumors, < 3 cm, with hepatic dysfunction severe enough to preclude them from resection. This treatment modality employs either cold (cryoablation) or heat (radiofrequency/microwave) to destroy tumors. Interventional radiologists and radiation oncologist also have effective treatments which can be offered to appropriate candidates.
Within the last several years, sorafenib, a multiple kinase inhibitor, was FDA approved for the treatment of unresectable hepatocellular carcinoma. In a randomized control trial, sorafenib was shown to increase survival over best supportive care.
With so many options now available for the treatment of hepatocellular carcinoma, trials are now underway to evaluate the effect of combining various treatments to obtain better long term survival. In addition, efforts are underway to educate the general population on the importance of screening high risk groups at regular intervals. By finding cancers earlier and having multiple tools to treat patients, new found hope has been given to curing this disease.
Dr. Christopher Siegel is an associate professor of Surgery, Case Western Reserve University, and Surgical Director, Liver Center of Excellence, Digestive Health Institute, University Hospitals Case Medical Center.
Reference
1. Siegel, R., Ward, E., Brawley, O., Jemal A., Cancer Statistics, 2011, CA Cancer J Clin 2011;61:212-236
Source
Saturday, November 12, 2011
Although hepatocellular carcinoma (HCC) does not garner the type of publicity breast cancer and colon cancer receive, it clearly remains a major cause of cancer mortality.
In the United States, the incidence of liver cancer remains the fifth and ninth leading cause of cancer deaths in men and women with an estimated 13,260 male and 6,330 female deaths in 2011. In contrast to the incidences of colon, lung and breast cancer, which are decreasing, the incidence of liver cancer is increasing.1
Studies (Davila et al, Gastroenterology, 2004) indicate this is in part due to the large number of people infected with viral hepatitis. Because of the latency between viral infection, cirrhosis, and the development of cancer, it has been projected that the number of hepatitis C related liver cancer cases will continue to rise and potentially double over the next 10-20 years (reviewed by El-Serag, Hepatology 2002).
The American Association for the Advancement of Liver Disease (AASLD) has developed recommendations for screening populations at risk. For chronic hepatitis B carriers, the guidelines recommend screening Asian males forty years of age or older, Asian females 50 years of age or older, all hepatitis B carriers with cirrhosis, all hepatitis B carriers with a family history of HCC and African hepatitis B carriers older than 20. Screening should also be offered to patients with cirrhosis related to hepatitis C, alcohol, hemochromatosis, and primary biliary cirrhosis.
Because patients who develop hepatocellular cancer often have cirrhosis as well, treatment algorithms and tumor staging systems have been developed to try to incorporate the degree of hepatic dysfunction in the recommendations for treatment.
For example, the treatment recommendation for a patient with a small tumor but with advanced cirrhosis may be different than a patient with the same size tumor but much better liver function and reserve. Multiple staging systems have been described to try to determine the best way to segregate patients to the appropriate treatment algorithm. One current commonly used algorithm is the Barcelona Clinic Liver Cancer (BCLC) staging classification. This staging system, Fig 1, takes into account underlying liver function as represented by the patient’s Child-Pugh-Turcotte score, as well as, tumor size, vascular involvement, the presence of extrahepatic disease and the patient’s performance status.
Multiple tools have been added to the armamentarium for the treatment of hepatocellular cancers. These can be separated into three categories: surgical, medical and radiological. Surgical options include resection, ablation and transplantation.
In a patient with HCC and no underlying cirrhosis, the goal should be resection if possible. In a study by Llovet et al. (Hepatology 1999), excellent five year survival rates were reported (74%) for patients with a normal bilirubin and no portal hypertension who were treated with resection. Arii et al. (Hepatology 2000) reported similar survival rates for 1,318 patients who underwent resection for the treatment of small (< 2 cm) hepatocellular cancers.
Most patients with hepatocellular cancers and early stage tumors are not candidates for resection based on poor underlying liver function and inadequate liver reserve. Based on a publication by Mazzaferro et al. (NEJM 1996) the United Network for Organ Sharing, UNOS, currently gives special consideration to patients who have a liver cancer that is less than 5 cm in size or have three or fewer tumors, no individual tumor larger than 3 cm. These criteria have become known as the Milan criteria. Patients that satisfy these requirements can be placed on the transplant list and are awarded enough points that they can often be transplanted relatively quickly. In Ohio they often can be transplanted within 3-6 months. Transplant recipients who met Milan criteria were found to have a 75% four year survival.
Ablation may be a possible treatment for patients with small tumors, < 3 cm, with hepatic dysfunction severe enough to preclude them from resection. This treatment modality employs either cold (cryoablation) or heat (radiofrequency/microwave) to destroy tumors. Interventional radiologists and radiation oncologist also have effective treatments which can be offered to appropriate candidates.
Within the last several years, sorafenib, a multiple kinase inhibitor, was FDA approved for the treatment of unresectable hepatocellular carcinoma. In a randomized control trial, sorafenib was shown to increase survival over best supportive care.
With so many options now available for the treatment of hepatocellular carcinoma, trials are now underway to evaluate the effect of combining various treatments to obtain better long term survival. In addition, efforts are underway to educate the general population on the importance of screening high risk groups at regular intervals. By finding cancers earlier and having multiple tools to treat patients, new found hope has been given to curing this disease.
Dr. Christopher Siegel is an associate professor of Surgery, Case Western Reserve University, and Surgical Director, Liver Center of Excellence, Digestive Health Institute, University Hospitals Case Medical Center.
Reference
1. Siegel, R., Ward, E., Brawley, O., Jemal A., Cancer Statistics, 2011, CA Cancer J Clin 2011;61:212-236
Source
ASN: HCV Infection Virtually Untreated in Dialysis Patients
By Todd Neale, Senior Staff Writer, MedPage Today
Published: November 12, 2011
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner
PHILADELPHIA -- Hepatitis C virus (HCV) infection is associated with an increase in mortality in patients on hemodialysis, but treatment is rare in that population, researchers found.
In a large, international cohort study of patients on hemodialysis, only one in every 100 of those who were HCV-positive received antiviral treatment, according to David Goodkin, MD, of the Arbor Research Collaborative for Health in Ann Arbor, Mich.
Treatment of HCV infection was associated a 73% lower risk of dying during follow-up, even after accounting for numerous potential confounders (HR 0.27, 95% CI 0.08 to 0.92), he reported at the American Society of Nephrology meeting here.
"We may be doing a disservice to our hemodialysis patients by not treating HCV, particularly those who are awaiting transplantation," Goodkin said.
A randomized trial examining the effect of treating HCV infection in patients on hemodialysis has not been done, and Goodkin said such a trial is unlikely because all previous trials of HCV treatments have excluded patients with renal failure.
But even if such a trial is undertaken, it would be years before conclusions could be drawn, he said.
"In the interim, clinicians are going to go on rounds, 10% of the patients are HCV-positive, and I really hope, at least for the transplant waiting list patients, [clinicians will] think again about whether [the patients] should be treated or not."
The findings came from a data analysis of the Dialysis Outcomes and Practice Patterns Study (DOPPS), a prospective cohort study of patients at 382 randomly selected hemodialysis clinics in 12 countries.
The current study included information on 47,004 patients participating in the study between 1996 and 2011. Median follow up ranged from 0.94 to 1.76 years.
The overall prevalence of HCV infection -- determined by a diagnosis of HCV infection in the medical record or a positive test for HCV antibodies at baseline or during follow-up -- was 9.6%, indicating that "this is not a trivial problem," according to Goodkin.
Overall, only 47 patients in the study (1.1% of those who were HCV-positive) were receiving antiviral medications. For patients on the kidney transplant waiting list who were HCV-positive, 3.8% were receiving antivirals.
Goodkin acknowledged that it is possible the use of antiviral medications was underestimated, but said that after calling some of the hemodialysis centers, he trusted the figures.
"Even if we were off by a factor of three, it's still almost no one is being treated," he said.
That is particularly important because HCV infection is associated with a 22% increased risk of mortality after adjustment for patient characteristics (HR 1.22, 95% CI 1.11 to 1.33), Goodkin said, noting that the hazards of death associated with congestive heart failure and diabetes are of similar magnitude.
HCV infection has also been shown to be associated with increased allograft loss, new-onset diabetes, serious infections, and death among untreated HCV-positive patients who had undergone a kidney transplant.
Treating HCV infection in patients on hemodialysis does work, Goodkin said, pointing to a systematic review that showed a 40% sustained virological response to interferon in those patients, which is comparable to or better than in the general population.
But antiviral therapy can be difficult for patients, which could account for the low treatment rates in patients on hemodialysis, who already have impaired quality of life, he noted.
Interferon is associated with flu-like symptoms, fatigue, depression, and neurological and cardiovascular complications. And ribavirin carries a risk of severe anemia.
Even so, Goodkin said guidelines from KDIGO (Kidney Disease: Improving Global Outcomes) addressed the issue correctly. Those recommendations state that HCV-positive patients who are awaiting a kidney transplant should receive antiviral treatment, whereas treatment in other patients should be considered on a case-by-case basis.
DOPPS is supported by Amgen, Kyowa Hakko Kirin, Abbott, Sanofi/Genzyme, and Baxter Healthcare without restrictions on publications.
Goodkin reported relationships with Affymax, AMAG, Amgen, Arbor Research Collaborative for Health, Cerevast, ChemoCentryx, FibroGen, Keryx, Seattle Life Sciences, Spectrum, Xenon (stock options), and Koronis (shareholder).
Primary source: American Society of Nephrology
Source reference:
Goodkin D, et al "Treatment of hepatitis C in hemodialysis patients is associated with markedly decreased mortality, but is rarely prescribed" ASN 2011; Abstract FR-OR281.
Source
Published: November 12, 2011
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner
PHILADELPHIA -- Hepatitis C virus (HCV) infection is associated with an increase in mortality in patients on hemodialysis, but treatment is rare in that population, researchers found.
In a large, international cohort study of patients on hemodialysis, only one in every 100 of those who were HCV-positive received antiviral treatment, according to David Goodkin, MD, of the Arbor Research Collaborative for Health in Ann Arbor, Mich.
Treatment of HCV infection was associated a 73% lower risk of dying during follow-up, even after accounting for numerous potential confounders (HR 0.27, 95% CI 0.08 to 0.92), he reported at the American Society of Nephrology meeting here.
"We may be doing a disservice to our hemodialysis patients by not treating HCV, particularly those who are awaiting transplantation," Goodkin said.
A randomized trial examining the effect of treating HCV infection in patients on hemodialysis has not been done, and Goodkin said such a trial is unlikely because all previous trials of HCV treatments have excluded patients with renal failure.
But even if such a trial is undertaken, it would be years before conclusions could be drawn, he said.
"In the interim, clinicians are going to go on rounds, 10% of the patients are HCV-positive, and I really hope, at least for the transplant waiting list patients, [clinicians will] think again about whether [the patients] should be treated or not."
The findings came from a data analysis of the Dialysis Outcomes and Practice Patterns Study (DOPPS), a prospective cohort study of patients at 382 randomly selected hemodialysis clinics in 12 countries.
The current study included information on 47,004 patients participating in the study between 1996 and 2011. Median follow up ranged from 0.94 to 1.76 years.
The overall prevalence of HCV infection -- determined by a diagnosis of HCV infection in the medical record or a positive test for HCV antibodies at baseline or during follow-up -- was 9.6%, indicating that "this is not a trivial problem," according to Goodkin.
Overall, only 47 patients in the study (1.1% of those who were HCV-positive) were receiving antiviral medications. For patients on the kidney transplant waiting list who were HCV-positive, 3.8% were receiving antivirals.
Goodkin acknowledged that it is possible the use of antiviral medications was underestimated, but said that after calling some of the hemodialysis centers, he trusted the figures.
"Even if we were off by a factor of three, it's still almost no one is being treated," he said.
That is particularly important because HCV infection is associated with a 22% increased risk of mortality after adjustment for patient characteristics (HR 1.22, 95% CI 1.11 to 1.33), Goodkin said, noting that the hazards of death associated with congestive heart failure and diabetes are of similar magnitude.
HCV infection has also been shown to be associated with increased allograft loss, new-onset diabetes, serious infections, and death among untreated HCV-positive patients who had undergone a kidney transplant.
Treating HCV infection in patients on hemodialysis does work, Goodkin said, pointing to a systematic review that showed a 40% sustained virological response to interferon in those patients, which is comparable to or better than in the general population.
But antiviral therapy can be difficult for patients, which could account for the low treatment rates in patients on hemodialysis, who already have impaired quality of life, he noted.
Interferon is associated with flu-like symptoms, fatigue, depression, and neurological and cardiovascular complications. And ribavirin carries a risk of severe anemia.
Even so, Goodkin said guidelines from KDIGO (Kidney Disease: Improving Global Outcomes) addressed the issue correctly. Those recommendations state that HCV-positive patients who are awaiting a kidney transplant should receive antiviral treatment, whereas treatment in other patients should be considered on a case-by-case basis.
DOPPS is supported by Amgen, Kyowa Hakko Kirin, Abbott, Sanofi/Genzyme, and Baxter Healthcare without restrictions on publications.
Goodkin reported relationships with Affymax, AMAG, Amgen, Arbor Research Collaborative for Health, Cerevast, ChemoCentryx, FibroGen, Keryx, Seattle Life Sciences, Spectrum, Xenon (stock options), and Koronis (shareholder).
Primary source: American Society of Nephrology
Source reference:
Goodkin D, et al "Treatment of hepatitis C in hemodialysis patients is associated with markedly decreased mortality, but is rarely prescribed" ASN 2011; Abstract FR-OR281.
Source
AASLD: MicroRNA Drug Safe in Ongoing HCV Study
By Michael Smith, North American Correspondent, MedPage Today
Published: November 12, 2011
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner
SAN FRANCISCO -- A novel hepatitis C virus (HCV) drug targeting genetic material in the liver was safe and well tolerated in a small, dose-finding clinical trial, a researcher said here.
Given as monotherapy, the compound, dubbed miravirsen, induced rapid dose-dependent reductions in the hepatitis C viral load, according to Harry Janssen, MD, of Erasmus Medical Center in Rotterdam, the Netherlands.
The reductions were sustained for more than a month after the end of therapy, Janssen reported at a late-breaker session during the annual meeting of the American Association for the Study of Liver Diseases.
Miravirsen "has the potential to eradicate" hepatitis C virus either alone or as part of an interferon-free regimen, Janssen concluded.
The compound blocks a host microRNA -- miR-122 -- that is critical to hepatitis C accumulation in the liver, Janssen said. MicroRNAs play important roles in gene regulation and expression and Janssen said miravirsen is the first drug to exploit a microRNA target for therapy.
Indeed, of the research presented at the late-breaker session, this study is " the most exciting because it is a whole new class of drug," said Norah Terrault, MD, of the University of California San Francisco, who was not part of the study but who was one of the moderators of the session.
For the study, Janssen said, researchers enrolled 36 patients with the difficult-to-treat genotype 1 of hepatitis C and assigned them to placebo or one of three doses of the drug -- 3, 5, and 7 mg/kg.
The patients, none of whom had been previously treated with pegylated interferon and ribavirin, were given five subcutaneous injections of the drug over four weeks and then followed for another 14 weeks.
The primary endpoint was safety and tolerability, Janssen said, with viral response as a second endpoint. Not all patients have completed the study, so the researchers reported data up to week 10, six weeks after the final dose.
Adverse events, he said, were "very much balanced" among the arms and over all "there were not a lot of side effects seen here." Most such events were mild and none led to stopping treatment, he added.
The only serious adverse event, in a patient receiving the high dose of the drug, was not considered related to treatment, he said.
In all three arms, the drug resulted in a significant drop in hepatitis C RNA levels, compared with placebo. Specifically:
• The low dose (3 mg/kg) led to a 0.57 IU/mL decline in viral load, which was significant at P=0.0334.
• The medium dose (5 mg/kg) yielded a drop of 2.16 IU/mL, which was significant at P=0.007.
• The high dose (7 mg/kg) led to a decline of 2.73 IU/mL, significant at P<0.001.
Although some patients in the low- and medium-dose arms had been allowed to begin treatment with peginterferon and ribavirin three weeks after their last dose of miravirsen, those taking the high dose were not allowed standard therapy until week 10.
Janssen said the drop in viral load seen with the high dose at week 10 "is a pure effect of miravirsen."
The downside of the drug, Terrault told MedPage Today, is that "it has to be given by injection, and that's always a challenging form of treatment."
On the other hand, it appears well tolerated and safe, with good efficacy, so "it might still be part of the mix" of treatment options. "I clearly get the sense it isn't going to be used solo," she said.
The study was supported by Santaris Pharma. Janssen reported financial links with the company and one author was employed by the company.
Terrault reported financial links with Gilead, Pfizer, Genentech, Roche, SciClone, BMS, Novartis, Eisai, and Vertex.
Primary source: Hepatology
Source reference:
Janssen HL, et al "A randomized, double-blind, placebo (PLB) controlled safety and anti-viral proof of concept study of miravirsen (MIR), an oligonucleotide targeting miR-122, in treatment naive patients with genotype 1 (GT1) chronic HCV infection" Hepatology 2011; Abstract LB-6.
Source
Published: November 12, 2011
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner
SAN FRANCISCO -- A novel hepatitis C virus (HCV) drug targeting genetic material in the liver was safe and well tolerated in a small, dose-finding clinical trial, a researcher said here.
Given as monotherapy, the compound, dubbed miravirsen, induced rapid dose-dependent reductions in the hepatitis C viral load, according to Harry Janssen, MD, of Erasmus Medical Center in Rotterdam, the Netherlands.
The reductions were sustained for more than a month after the end of therapy, Janssen reported at a late-breaker session during the annual meeting of the American Association for the Study of Liver Diseases.
Miravirsen "has the potential to eradicate" hepatitis C virus either alone or as part of an interferon-free regimen, Janssen concluded.
The compound blocks a host microRNA -- miR-122 -- that is critical to hepatitis C accumulation in the liver, Janssen said. MicroRNAs play important roles in gene regulation and expression and Janssen said miravirsen is the first drug to exploit a microRNA target for therapy.
Indeed, of the research presented at the late-breaker session, this study is " the most exciting because it is a whole new class of drug," said Norah Terrault, MD, of the University of California San Francisco, who was not part of the study but who was one of the moderators of the session.
For the study, Janssen said, researchers enrolled 36 patients with the difficult-to-treat genotype 1 of hepatitis C and assigned them to placebo or one of three doses of the drug -- 3, 5, and 7 mg/kg.
The patients, none of whom had been previously treated with pegylated interferon and ribavirin, were given five subcutaneous injections of the drug over four weeks and then followed for another 14 weeks.
The primary endpoint was safety and tolerability, Janssen said, with viral response as a second endpoint. Not all patients have completed the study, so the researchers reported data up to week 10, six weeks after the final dose.
Adverse events, he said, were "very much balanced" among the arms and over all "there were not a lot of side effects seen here." Most such events were mild and none led to stopping treatment, he added.
The only serious adverse event, in a patient receiving the high dose of the drug, was not considered related to treatment, he said.
In all three arms, the drug resulted in a significant drop in hepatitis C RNA levels, compared with placebo. Specifically:
• The low dose (3 mg/kg) led to a 0.57 IU/mL decline in viral load, which was significant at P=0.0334.
• The medium dose (5 mg/kg) yielded a drop of 2.16 IU/mL, which was significant at P=0.007.
• The high dose (7 mg/kg) led to a decline of 2.73 IU/mL, significant at P<0.001.
Although some patients in the low- and medium-dose arms had been allowed to begin treatment with peginterferon and ribavirin three weeks after their last dose of miravirsen, those taking the high dose were not allowed standard therapy until week 10.
Janssen said the drop in viral load seen with the high dose at week 10 "is a pure effect of miravirsen."
The downside of the drug, Terrault told MedPage Today, is that "it has to be given by injection, and that's always a challenging form of treatment."
On the other hand, it appears well tolerated and safe, with good efficacy, so "it might still be part of the mix" of treatment options. "I clearly get the sense it isn't going to be used solo," she said.
The study was supported by Santaris Pharma. Janssen reported financial links with the company and one author was employed by the company.
Terrault reported financial links with Gilead, Pfizer, Genentech, Roche, SciClone, BMS, Novartis, Eisai, and Vertex.
Primary source: Hepatology
Source reference:
Janssen HL, et al "A randomized, double-blind, placebo (PLB) controlled safety and anti-viral proof of concept study of miravirsen (MIR), an oligonucleotide targeting miR-122, in treatment naive patients with genotype 1 (GT1) chronic HCV infection" Hepatology 2011; Abstract LB-6.
Source
AASLD: New PI Effective, Safe in HCV Trial
By Michael Smith, North American Correspondent, MedPage Today
Published: November 13, 2011
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner
SAN FRANCISCO -- An investigational hepatitis C virus (HCV) drug -- a second-generation protease inhibitor given once a day -- was safe and effective in a phase IIB randomized trial, a researcher said here.
Between 75% and 86% of patients treated with TMC435 had undetectable hepatitis C RNA after 24 weeks of treatment, depending on dose, reported Michael Fried, MD, of the University of North Carolina in Chapel Hill.
In addition, there was no major difference in adverse events between the treatment and placebo arms in the PILLAR (Protease Inhibitor TMC435 trial assessing the optimaL dose and duration as once daiLy Anti-viral Regimen) trial, Fried said at a late-breaker session during the annual meeting of the American Association for the Study of Liver Diseases.
The primary endpoint of the study was the proportion of patients with undetectable hepatitis C RNA at week 72, which was 24 weeks after the end of treatment, Fried said. However, his presentation here focused on what he said was "the most clinically meaningful endpoint," which was the rate of undetectable hepatitis C RNA at week 24.
The researchers enrolled 386 patients with the difficult-to-treat genotype 1 of hepatitis C and randomly assigned them to placebo or one of two doses of TMC435: 75 or 150 mg daily.
All patients were also given standard therapy with pegylated interferon-alfa and ribavirin for at least the first 24 weeks of the study. Depending on response, some patients in the treatment arms stopped the treatment or were given an additional 24 weeks. Patients in the control arm had 48 weeks of interferon and ribavirin.
Within each TMC435 dosing group, patients were randomly assigned to get 12 or 24 weeks of the drug.
In an intention-to-treat analysis, the researchers found:
• 82% of patients in the 12-week, 75-mg arm had undetectable hepatitis C RNA after 24 weeks.
• In the 150-mg dosing group, 81% in the 12-week arm and 86% in the 24-week arm reached the same endpoint.
• The differences from placebo were significant at P<0.005, P=0.013, and P<0.001, respectively.
Interestingly, the 75% response in the 24-week, 75-mg arm was not significantly different from the "unexpectedly high" 65% response rate among the placebo patients, Fried said.
A key finding was that between 79% and 86% of the patients receiving the drug qualified for shortened 24-week therapy, "which I think is quite beneficial," Fried said. Of those, he said, between 85% and 96% had undetectable hepatitis C RNA at week 24.
All patients had at least one adverse event, Fried said, with 3.6% of such events leading to study discontinuation in the TMC435 arms, compared with 5.2% in the control arm. The rate of grades 3 and 4 events was similar between the treatment and placebo arms. However, 6.5% of adverse events were judged as serious in the TMC435 group compared with 13% among placebo patients.
Most adverse events, including rash, anemia, and neutropenia, were similar between the arms.
The compound is the "front-runner" in the second generation of protease inhibitors and clinicians are watching its progress closely, according to Norah Terrault, MD, of the University of California San Francisco, who was not part of the study but was one of the moderators of the session at which it was presented.
"This is the next step for us if we are going to use peginterferon and ribavirin," she told MedPage Today. "It is clearly going to offer an advantage over current therapies."
One advantage, she said, is that once-daily dosing -- compared with three times a day for the currently approved drugs -- should improve patient adherence to their treatment regimen.
As well, she added, the "side effect profile looks very good" with no additional burden of rash or anemia.
On the other hand, a range of new drugs is in development and some can be given without interferon. Clinicians may soon be able to choose interferon-free strategies to treat hepatitis C, Terrault said.
The study was supported by Tibotec. Fried reported financial links with GSK, Roche, Merck, Tibotec, Vertex, Abbott, Pharmasset, Anadys, and Bristol-Myers Squibb.
Terrault reported financial links with Gilead, Pfizer, Genentech, Roche, SciClone, BMS, Novartis, Essai, and Vertex.
Primary source: Hepatology
Source reference:
Fried M, et al "TMC435 in combination with peginterferon and ribavarin in treatment-naive HCV genotype 1 patients: final analysis of the PILLAR Phase IIB study" Hepatology 2011; Abstract LB-5.
Source
Published: November 13, 2011
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner
SAN FRANCISCO -- An investigational hepatitis C virus (HCV) drug -- a second-generation protease inhibitor given once a day -- was safe and effective in a phase IIB randomized trial, a researcher said here.
Between 75% and 86% of patients treated with TMC435 had undetectable hepatitis C RNA after 24 weeks of treatment, depending on dose, reported Michael Fried, MD, of the University of North Carolina in Chapel Hill.
In addition, there was no major difference in adverse events between the treatment and placebo arms in the PILLAR (Protease Inhibitor TMC435 trial assessing the optimaL dose and duration as once daiLy Anti-viral Regimen) trial, Fried said at a late-breaker session during the annual meeting of the American Association for the Study of Liver Diseases.
The primary endpoint of the study was the proportion of patients with undetectable hepatitis C RNA at week 72, which was 24 weeks after the end of treatment, Fried said. However, his presentation here focused on what he said was "the most clinically meaningful endpoint," which was the rate of undetectable hepatitis C RNA at week 24.
The researchers enrolled 386 patients with the difficult-to-treat genotype 1 of hepatitis C and randomly assigned them to placebo or one of two doses of TMC435: 75 or 150 mg daily.
All patients were also given standard therapy with pegylated interferon-alfa and ribavirin for at least the first 24 weeks of the study. Depending on response, some patients in the treatment arms stopped the treatment or were given an additional 24 weeks. Patients in the control arm had 48 weeks of interferon and ribavirin.
Within each TMC435 dosing group, patients were randomly assigned to get 12 or 24 weeks of the drug.
In an intention-to-treat analysis, the researchers found:
• 82% of patients in the 12-week, 75-mg arm had undetectable hepatitis C RNA after 24 weeks.
• In the 150-mg dosing group, 81% in the 12-week arm and 86% in the 24-week arm reached the same endpoint.
• The differences from placebo were significant at P<0.005, P=0.013, and P<0.001, respectively.
Interestingly, the 75% response in the 24-week, 75-mg arm was not significantly different from the "unexpectedly high" 65% response rate among the placebo patients, Fried said.
A key finding was that between 79% and 86% of the patients receiving the drug qualified for shortened 24-week therapy, "which I think is quite beneficial," Fried said. Of those, he said, between 85% and 96% had undetectable hepatitis C RNA at week 24.
All patients had at least one adverse event, Fried said, with 3.6% of such events leading to study discontinuation in the TMC435 arms, compared with 5.2% in the control arm. The rate of grades 3 and 4 events was similar between the treatment and placebo arms. However, 6.5% of adverse events were judged as serious in the TMC435 group compared with 13% among placebo patients.
Most adverse events, including rash, anemia, and neutropenia, were similar between the arms.
The compound is the "front-runner" in the second generation of protease inhibitors and clinicians are watching its progress closely, according to Norah Terrault, MD, of the University of California San Francisco, who was not part of the study but was one of the moderators of the session at which it was presented.
"This is the next step for us if we are going to use peginterferon and ribavirin," she told MedPage Today. "It is clearly going to offer an advantage over current therapies."
One advantage, she said, is that once-daily dosing -- compared with three times a day for the currently approved drugs -- should improve patient adherence to their treatment regimen.
As well, she added, the "side effect profile looks very good" with no additional burden of rash or anemia.
On the other hand, a range of new drugs is in development and some can be given without interferon. Clinicians may soon be able to choose interferon-free strategies to treat hepatitis C, Terrault said.
The study was supported by Tibotec. Fried reported financial links with GSK, Roche, Merck, Tibotec, Vertex, Abbott, Pharmasset, Anadys, and Bristol-Myers Squibb.
Terrault reported financial links with Gilead, Pfizer, Genentech, Roche, SciClone, BMS, Novartis, Essai, and Vertex.
Primary source: Hepatology
Source reference:
Fried M, et al "TMC435 in combination with peginterferon and ribavarin in treatment-naive HCV genotype 1 patients: final analysis of the PILLAR Phase IIB study" Hepatology 2011; Abstract LB-5.
Source
AASLD: Platelet Booster Aids HCV Therapy
By Charles Bankhead, Staff Writer, MedPage Today
Published: November 14, 2011
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner
SAN FRANCISCO -- Patients with chronic hepatitis C virus (HCV) infection and thrombocytopenia had significant improvement in virologic response when pegylated interferon alpha 2a (Pegasys) was given with eltrombopag (Promacta), results of a randomized trial showed.
Overall, 66% of patients treated with eltrombopag plus peginterferon alpha 2a and ribavirin had an early virologic response compared with 50% of patients who received peginterferon 2a, ribavirin, and a placebo (P<0.0001). Additionally, 23% of the eltrombopag group achieved a sustained virologic response versus 14% of the placebo group (P=0.0064).
Treatment with eltrombopag was associated with an increased time-to-first-dose reduction of peginterferon and with fewer dose reductions, as reported here at the American Association for the Study of Liver Diseases meeting.
"Eltrombopag treatment enabled the introduction of antiviral therapy in 95% of patients who would otherwise be marginal candidates for pegylated interferon 2-alpha therapy," said Nezam H. Afdhal, MD, of Harvard and Beth Israel Deaconess Medical Center in Boston.
"Treatment with eltrombopag provided a statistically significant and clinically meaningful improvement in sustained virologic response versus placebo."
"Eltrombopag showed an acceptable safety profile in high-risk patients with cirrhosis," he added.
Preliminary data from a companion study demonstrated similar improvement in early and sustained virologic response when eltrombopag was administered with peginterferon alpha 2b (PEG-Intron).
Patients with advanced liver fibrosis and portal hypertension frequently develop thrombocytopenia, which usually precludes antiviral therapy. Recommended platelet counts for initiation of peginterferon alpha 2a or 2b are ≥90,000/µL and ≥100,000/µL, respectively. Platelet counts commonly decline during peginterferon therapy as a result of myelosuppression.
Eltrombopag is an oral thrombopoietin receptor agonist that increases platelet count by increasing megakaryocyte differentiation and proliferation, Afdhal noted. The drug is approved in the U.S. for second-line treatment of chronic idiopathic thrombocytopenic purpura.
Investigators in two international randomized, placebo-controlled clinical trials sought to determine whether use of eltrombopag would enable patients with HCV infection, advanced liver fibrosis, and thrombocytopenia to receive peginterferon alpha 2a (ENABLE 1) or 2b (ENABLE 2).
Afdhal reported final results from ENABLE 1 and provided a glimpse of the initial results from ENABLE 2.
ENABLE 1 investigators enrolled patients who had HCV cirrhosis and platelet counts <75,000/µL. The trial had two phases. During the first phase, all patients received open-label eltrombopag at a starting dose of 25 mg, which was titrated to a maximum dose of 100 mg or until a platelet count of ≥90,000/µL was reached.
Patients who achieved the platelet threshold entered the randomized phase of the study, wherein they were allocated 2:1 to receive eltrombopag or placebo, in addition to peginterferon alpha 2a and ribavirin. Patients with HCV genotype 2 or 3 continued treatment for 24 weeks; all others were treated for 48 weeks. The primary endpoint was sustained virologic response.
Afdhal reported that 715 patients entered the open-label phase of the study and had a median baseline platelet count of 59,000/µL, increasing to 89,000/µL by the end of open-label eltrombopag therapy.
Subsequently, 682 patients initiated randomized therapy. They had a median baseline platelet count of about 130,000/µL. After four weeks of treatment, the median platelet count had decreased to 90,000/µL in the eltrombopag arm and to 43,500/µL in the placebo group.
The median platelet count remained >80,000/µL throughout the study in the eltrombopag arm and <50,000/µL in the placebo arm.
In addition to the intention-to-treat analysis, subgroup analyses by HCV genotype showed a consistent difference between groups in favor of eltrombopag. Among genotype 1 patients (N=462), 58% of the eltrombopag group versus 41% of the placebo group had an early virologic response, and 18% versus 10%, respectively, had a sustained virologic response.
Among genotype 2/3 patients, early virologic response occurred in 84% of the eltrombopag group versus 67% of the placebo group and sustained virologic response in 35% versus 24%, respectively.
Afdhal said that 57% of eltrombopag patients required no peginterferon alpha 2a dose reductions, as compared with 30% of the placebo group. Treatment with the thrombopoietin agonist was associated with significant prolongation of the time to first peginterferon dose reduction (P<0.0001).
Adverse events, serious adverse events, and drug-related adverse events occurred in a similar proportion of patients in the two treatment groups. The most common adverse events in both groups were anemia, neutropenia, fatigue, pyrexia, and headache. Thrombotic adverse events occurred in 2% of patients in each group.
A preliminary intention-to-treat analysis of data from ENABLE 2 showed that 62% of eltrombopag-treated patients had an early virologic response compared with 41% of the placebo group (P<0.0001) and sustained virologic response in 19% and 13% of patients, respectively (P=0.020).
"Sustained virologic response rates remain constrained by a lack of interferon efficacy in patients with advanced disease," Afdhal said.
The study was supported by GlaxoSmithKline.
Afdhal disclosed relationships with Merck, Novartis, GlaxoSmithKline, Echosens, Vertex, Gilead, Quest, Pharmasett, Abbott, Biogen, Idera Pharmaceuticals, Boehringer Ingelheim, Human Genome Sciences, Biodex, Fibrogen, Ligand, and Springbank.
Primary source: American Association for the Study of Liver Diseases
Source reference:
Afdhal NH, et al "Final results of ENABLE 1, a phase III, multicenter study of eltrombopag as an adjunct for antiviral treatment of hepatitis C virus-related chronic liver disease associated with thrombocytopenia" AASLD 2011; Abstract LB-3.
Source
Published: November 14, 2011
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner
SAN FRANCISCO -- Patients with chronic hepatitis C virus (HCV) infection and thrombocytopenia had significant improvement in virologic response when pegylated interferon alpha 2a (Pegasys) was given with eltrombopag (Promacta), results of a randomized trial showed.
Overall, 66% of patients treated with eltrombopag plus peginterferon alpha 2a and ribavirin had an early virologic response compared with 50% of patients who received peginterferon 2a, ribavirin, and a placebo (P<0.0001). Additionally, 23% of the eltrombopag group achieved a sustained virologic response versus 14% of the placebo group (P=0.0064).
Treatment with eltrombopag was associated with an increased time-to-first-dose reduction of peginterferon and with fewer dose reductions, as reported here at the American Association for the Study of Liver Diseases meeting.
"Eltrombopag treatment enabled the introduction of antiviral therapy in 95% of patients who would otherwise be marginal candidates for pegylated interferon 2-alpha therapy," said Nezam H. Afdhal, MD, of Harvard and Beth Israel Deaconess Medical Center in Boston.
"Treatment with eltrombopag provided a statistically significant and clinically meaningful improvement in sustained virologic response versus placebo."
"Eltrombopag showed an acceptable safety profile in high-risk patients with cirrhosis," he added.
Preliminary data from a companion study demonstrated similar improvement in early and sustained virologic response when eltrombopag was administered with peginterferon alpha 2b (PEG-Intron).
Patients with advanced liver fibrosis and portal hypertension frequently develop thrombocytopenia, which usually precludes antiviral therapy. Recommended platelet counts for initiation of peginterferon alpha 2a or 2b are ≥90,000/µL and ≥100,000/µL, respectively. Platelet counts commonly decline during peginterferon therapy as a result of myelosuppression.
Eltrombopag is an oral thrombopoietin receptor agonist that increases platelet count by increasing megakaryocyte differentiation and proliferation, Afdhal noted. The drug is approved in the U.S. for second-line treatment of chronic idiopathic thrombocytopenic purpura.
Investigators in two international randomized, placebo-controlled clinical trials sought to determine whether use of eltrombopag would enable patients with HCV infection, advanced liver fibrosis, and thrombocytopenia to receive peginterferon alpha 2a (ENABLE 1) or 2b (ENABLE 2).
Afdhal reported final results from ENABLE 1 and provided a glimpse of the initial results from ENABLE 2.
ENABLE 1 investigators enrolled patients who had HCV cirrhosis and platelet counts <75,000/µL. The trial had two phases. During the first phase, all patients received open-label eltrombopag at a starting dose of 25 mg, which was titrated to a maximum dose of 100 mg or until a platelet count of ≥90,000/µL was reached.
Patients who achieved the platelet threshold entered the randomized phase of the study, wherein they were allocated 2:1 to receive eltrombopag or placebo, in addition to peginterferon alpha 2a and ribavirin. Patients with HCV genotype 2 or 3 continued treatment for 24 weeks; all others were treated for 48 weeks. The primary endpoint was sustained virologic response.
Afdhal reported that 715 patients entered the open-label phase of the study and had a median baseline platelet count of 59,000/µL, increasing to 89,000/µL by the end of open-label eltrombopag therapy.
Subsequently, 682 patients initiated randomized therapy. They had a median baseline platelet count of about 130,000/µL. After four weeks of treatment, the median platelet count had decreased to 90,000/µL in the eltrombopag arm and to 43,500/µL in the placebo group.
The median platelet count remained >80,000/µL throughout the study in the eltrombopag arm and <50,000/µL in the placebo arm.
In addition to the intention-to-treat analysis, subgroup analyses by HCV genotype showed a consistent difference between groups in favor of eltrombopag. Among genotype 1 patients (N=462), 58% of the eltrombopag group versus 41% of the placebo group had an early virologic response, and 18% versus 10%, respectively, had a sustained virologic response.
Among genotype 2/3 patients, early virologic response occurred in 84% of the eltrombopag group versus 67% of the placebo group and sustained virologic response in 35% versus 24%, respectively.
Afdhal said that 57% of eltrombopag patients required no peginterferon alpha 2a dose reductions, as compared with 30% of the placebo group. Treatment with the thrombopoietin agonist was associated with significant prolongation of the time to first peginterferon dose reduction (P<0.0001).
Adverse events, serious adverse events, and drug-related adverse events occurred in a similar proportion of patients in the two treatment groups. The most common adverse events in both groups were anemia, neutropenia, fatigue, pyrexia, and headache. Thrombotic adverse events occurred in 2% of patients in each group.
A preliminary intention-to-treat analysis of data from ENABLE 2 showed that 62% of eltrombopag-treated patients had an early virologic response compared with 41% of the placebo group (P<0.0001) and sustained virologic response in 19% and 13% of patients, respectively (P=0.020).
"Sustained virologic response rates remain constrained by a lack of interferon efficacy in patients with advanced disease," Afdhal said.
The study was supported by GlaxoSmithKline.
Afdhal disclosed relationships with Merck, Novartis, GlaxoSmithKline, Echosens, Vertex, Gilead, Quest, Pharmasett, Abbott, Biogen, Idera Pharmaceuticals, Boehringer Ingelheim, Human Genome Sciences, Biodex, Fibrogen, Ligand, and Springbank.
Primary source: American Association for the Study of Liver Diseases
Source reference:
Afdhal NH, et al "Final results of ENABLE 1, a phase III, multicenter study of eltrombopag as an adjunct for antiviral treatment of hepatitis C virus-related chronic liver disease associated with thrombocytopenia" AASLD 2011; Abstract LB-3.
Source
Interferon-Free Alisporivir Treatment Showing Promise in Genotype 2/3 Trial
November 14, 2011
Alisporivir, a once-daily drug being developed by Novartis at the forefront of a new class of hepatitis C virus (HCV) compounds known as cyclophilin inhibitors, is showing promise as a component of interferon-free therapy for people with genotype 2 or 3 HCV infection, according to new results from a Phase II study reported in San Francisco at the 62nd annual meeting of the American Association for the Study of Liver Diseases.
Nearly half of all study volunteers using the drug in combination with ribavirin, but without interferon, have undetectable HCV levels after six weeks of treatment, reported Jean-Michel Pawlotsky, MD, of the University of East Paris and his colleagues. In addition, roughly a third of the genotype 2/3 patients in the study had undetectable HCV levels at the six-week mark of therapy with alisporivir alone—use of the drug without either pegylated interferon or ribavirin.
Also known as DEB025, alisporivir works by inhibiting a cellular protein called cyclophilin known to play a role in the reproduction of HCV. The drug is similar to—and actually synthesized from—cyclosporin A, a compound used to suppress the immune system during organ transplants to prevent the body from rejecting the organ. Alisporivir does not, however, suppress the immune system. And because alisporivir targets a cellular protein used by all types of HCV, it may prove to be an effective option against a broad range of HCV genotypes and less susceptible to drug resistance.
The clinical trial reported by Pawlotsky’s team has enrolled about 340 previously untreated people living with genotype 2 or 3 HCV infection. Five groups are being compared in the study. Two groups are receiving alisporivir—either 600 milligrams (mg) or 800 mg once daily—plus ribavirin (400 mg twice daily). A third group is receiving alisporivir (600 mg once daily) plus once-weekly pegylated interferon. A fourth group is receiving standard therapy: pegylated interferon plus twice-daily ribavirin. A fifth group is receiving 1,000 mg alisporivir monotherapy.
Only interim data—all participants in the study remain on treatment—were reported by Pawlotsky’s group. Final results—rates of sustained virologic responses (SVR)s, or viral cures—will be available once therapy is discontinued and study volunteers have been off treatment for 24 weeks.
Six weeks into treatment, 49 percent of those receiving alisporivir plus ribavirin have undetectable HCV levels. In addition, 97 percent of those who had undetectable viral loads at six weeks in the alisporivir/ribavirin groups and had been followed for at least 12 weeks of treatment maintained HCV viral loads below the level of detection.
Also encouraging, 32 percent of those receiving alisporivir alone also have viral loads below the level of detection after six weeks of treatment.
Response rates are thus far similar in the two alisporivir/ribavirin treatment groups—51 percent of those in the 600 mg group had undetectable viral loads at six weeks, compared with 48 percent of those in the 800 mg group. Interim response rates are also similar among those with genotype 2 versus genotype 3 HCV.
Of note, participants receiving alisporivir/ribavirin or alisporivir monotherapy who have detectable HCV levels after four weeks of treatment are receiving add-on pegylated interferon (or pegylated interferon/ribavirin) therapy from week six onward. For those who have met these criteria, as little as two weeks of add-on treatment reduced HCV viral loads to undetectable in more than 85 percent.
Thus far, there has been a low incidence of serious side effects, with rates of adverse events comparable between the treatment groups. A low number of people experienced an increase in bilirubin, a pigment found in the liver, which can cause yellowing of the skin, nails and eyes. Increased bilirubin can also be a sign of liver damage. However, according to Pawlotsky, the bilirubin increases seen in patients receiving alisporivir have not been associated with any other signs of liver damage.
A Phase III study of alisporivir evaluating its safety and effectiveness, when combined with pegylated interferon and ribavirin, for people with hard-to-treat genotype 1 HCV infection is currently under way. Preliminary Phase II data involving this population of patients were reported earlier this year in Berlin at the 46th Annual Meeting of the European Association for the Study of the Liver.
Other studies are being conducted as well, including Phase II evaluations involving people with genotype 1 HCV who tried and failed earlier treatment.
Source
Alisporivir, a once-daily drug being developed by Novartis at the forefront of a new class of hepatitis C virus (HCV) compounds known as cyclophilin inhibitors, is showing promise as a component of interferon-free therapy for people with genotype 2 or 3 HCV infection, according to new results from a Phase II study reported in San Francisco at the 62nd annual meeting of the American Association for the Study of Liver Diseases.
Nearly half of all study volunteers using the drug in combination with ribavirin, but without interferon, have undetectable HCV levels after six weeks of treatment, reported Jean-Michel Pawlotsky, MD, of the University of East Paris and his colleagues. In addition, roughly a third of the genotype 2/3 patients in the study had undetectable HCV levels at the six-week mark of therapy with alisporivir alone—use of the drug without either pegylated interferon or ribavirin.
Also known as DEB025, alisporivir works by inhibiting a cellular protein called cyclophilin known to play a role in the reproduction of HCV. The drug is similar to—and actually synthesized from—cyclosporin A, a compound used to suppress the immune system during organ transplants to prevent the body from rejecting the organ. Alisporivir does not, however, suppress the immune system. And because alisporivir targets a cellular protein used by all types of HCV, it may prove to be an effective option against a broad range of HCV genotypes and less susceptible to drug resistance.
The clinical trial reported by Pawlotsky’s team has enrolled about 340 previously untreated people living with genotype 2 or 3 HCV infection. Five groups are being compared in the study. Two groups are receiving alisporivir—either 600 milligrams (mg) or 800 mg once daily—plus ribavirin (400 mg twice daily). A third group is receiving alisporivir (600 mg once daily) plus once-weekly pegylated interferon. A fourth group is receiving standard therapy: pegylated interferon plus twice-daily ribavirin. A fifth group is receiving 1,000 mg alisporivir monotherapy.
Only interim data—all participants in the study remain on treatment—were reported by Pawlotsky’s group. Final results—rates of sustained virologic responses (SVR)s, or viral cures—will be available once therapy is discontinued and study volunteers have been off treatment for 24 weeks.
Six weeks into treatment, 49 percent of those receiving alisporivir plus ribavirin have undetectable HCV levels. In addition, 97 percent of those who had undetectable viral loads at six weeks in the alisporivir/ribavirin groups and had been followed for at least 12 weeks of treatment maintained HCV viral loads below the level of detection.
Also encouraging, 32 percent of those receiving alisporivir alone also have viral loads below the level of detection after six weeks of treatment.
Response rates are thus far similar in the two alisporivir/ribavirin treatment groups—51 percent of those in the 600 mg group had undetectable viral loads at six weeks, compared with 48 percent of those in the 800 mg group. Interim response rates are also similar among those with genotype 2 versus genotype 3 HCV.
Of note, participants receiving alisporivir/ribavirin or alisporivir monotherapy who have detectable HCV levels after four weeks of treatment are receiving add-on pegylated interferon (or pegylated interferon/ribavirin) therapy from week six onward. For those who have met these criteria, as little as two weeks of add-on treatment reduced HCV viral loads to undetectable in more than 85 percent.
Thus far, there has been a low incidence of serious side effects, with rates of adverse events comparable between the treatment groups. A low number of people experienced an increase in bilirubin, a pigment found in the liver, which can cause yellowing of the skin, nails and eyes. Increased bilirubin can also be a sign of liver damage. However, according to Pawlotsky, the bilirubin increases seen in patients receiving alisporivir have not been associated with any other signs of liver damage.
A Phase III study of alisporivir evaluating its safety and effectiveness, when combined with pegylated interferon and ribavirin, for people with hard-to-treat genotype 1 HCV infection is currently under way. Preliminary Phase II data involving this population of patients were reported earlier this year in Berlin at the 46th Annual Meeting of the European Association for the Study of the Liver.
Other studies are being conducted as well, including Phase II evaluations involving people with genotype 1 HCV who tried and failed earlier treatment.
Source
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