Liver Transplantation Improves Symptoms in Patients With Cirrhosis-Related Parkinsonism: Presented at EFNS
By Jenny Powers
GENEVA -- September 28, 2010 -- Patients with cirrhosis-related parkinsonism have improved overall symptoms after liver transplantation, according to preliminary data from a study presented here at the 14th Congress of the European Federation of Neurological Societies (EFNS).
A form of chronic parkinsonism associated with liver cirrhosis is rapidly evolving and involves symmetrical akinetic-rigid syndrome, gait and postural impairment, and focal dystonia. Unlike classic Parkinson's disease, resting tremor is notably minimal or absent in this form of parkinsonism, but postural tremor is prominent.
Diana Apetauerova, MD, Lahey Clinic, Burlington, Massachusetts, presented the findings on September 26. The researchers are conducting an ongoing trial to determine the relationship between the neuroradiological and biological aspects of parkinsonism and liver cirrhosis severity.
Cirrhosis-related parkinsonism is seen in acquired hepatocerebral degeneration, but its prevalence and post-transplant natural history have not been determined. This prospective study will enrol up to 120 patients with liver cirrhosis who were treated at the Lahey Clinic liver-transplant facility.
Parkinsonism is being evaluated by use of the United Parkinson's Disease Rating Scale (UPDRS), brain magnetic resonance imaging, Mini-Mental State Examination, and videotaping. Patients are also undergoing standard liver transplant evaluation and repeat testing at 6 weeks and 3 and 12 months after transplantation.
The researchers examined the possible correlations between the severity of liver disease, determined by the Model for End-Stage Liver Disease (MELD) scale, and the stage of parkinsonism, determined by the motor part of UPDRS.
Of the patients with cirrhotic liver disease, 46% (38 of 81) exhibited parkinsonism. No association was seen between the severity of MELD and motor UPDRS (P = .74) or increased copper, ammonia, manganese, or iron levels. Abnormal signal in the basal ganglia was seen in all of the patients with parkinsonism.
Seven parkinsonian patients underwent liver transplantation. At 3 months after surgery, statistically significant improvement was seen in several aspects of parkinsonism, specifically gait (P = .02), total motor UPDRS (P = .03), and activities of daily living (P = .06).
Dr. Apetauerova concluded that this study identified a high incidence of parkinsonism in patients with liver cirrhosis. Although no correlations were found between the severity of liver cirrhosis and the severity of symptoms, a statistically significant improvement was observed in symptoms after liver transplantation.
The ongoing study has accumulated substantial data that have yet to be analysed, Dr. Apetauerova said. One aspect that will be retrospectively investigated is the effect of portal systemic shunting.
[Presentation title: Chronic Parkinsonism Associated With Liver Cirrhosis. Abstract P1671]
http://www.docguide.com/news/content.nsf/news/852576140048867C852577AC007702A1
Thursday, September 30, 2010
What sort of problems can I have if I have cirrhosis?
Damaged livers, ruined lives
By Dr Y.L.M.
MY father had a hepatitis B infection once. Recently, he had an ultrasound done as part of a routine check-up, and the report came out that his liver had cirrhosis. What is cirrhosis?
Cirrhosis of the liver is what happens to your liver as a complication of many diseases. It is how your liver looks anatomically - with a lot of scar tissue manifested in nodules and fibrous tissue that is hard.
This is what happens to your liver:
By Dr Y.L.M.
MY father had a hepatitis B infection once. Recently, he had an ultrasound done as part of a routine check-up, and the report came out that his liver had cirrhosis. What is cirrhosis?
Cirrhosis of the liver is what happens to your liver as a complication of many diseases. It is how your liver looks anatomically - with a lot of scar tissue manifested in nodules and fibrous tissue that is hard.
This is what happens to your liver:
Recall/Anemia drugs Procrit and Epogen
Amgen, J&J anemia drugs recalled over glass flakes
By Deena Beasley
LOS ANGELES Fri Sep 24, 2010 2:09pm EDT
LOS ANGELES (Reuters) - Amgen Inc is recalling several hundred lots of anemia drugs Epogen and Procrit, sold by Johnson & Johnson, because vials of the injectable medicines might develop tiny glass flakes that could cause blood clots and other serious health problems.
Amgen, which sells Epogen, manufactures the identical drugs at a plant in Puerto Rico.
Amgen spokeswoman Emma Hurley said the recall, which included 200 lots of Epogen, is not expected to disrupt availability of the drug and the biotechnology company does not expect a material financial impact.
J&J spokeswoman Lisa Vaga said 155 lots of Procrit were recalled, but declined to comment on any financial impact to the company.
Amgen said there have been no patient complaints that can be directly attributed to the presence of glass. It said the lots were being voluntarily recalled as a precaution.
The glass flakes result from the interaction of the drug with glass vials over the shelf life of the product, the company said.
Hurley said expiration dates for the drugs have been reduced to 12 months for single-dose vials and 15 months for multi-dose vials. Their shelf life had been 36 months.
She also said the company would switch vial manufacturers.
"From an investor standpoint, I don't think there's any real impact at all," said Cowen & Co analyst Eric Schmidt. "There's no patient safety issue, no one's been harmed here. There's no supply issue. There will be plenty of supply to go around."
Amgen sells Epogen in the United States, where it is used mostly for kidney dialysis patients. Under a long-standing license from Amgen, J&J's Centocor Ortho Biotech unit distributes Procrit in the United States, mainly for cancer and HIV patients. J&J has been dealing with a rash of recalls of its consumer medicines.
Biotechnology company Genzyme Corp has had its reputation damaged by product shortages caused by manufacturing quality control issues.
Since the Amgen recall relates to materials rather than production processes, the impact on the company will be much more limited, said Bernstein & Co analyst Geoffrey Porges.
Amgen said the recall is being conducted in cooperation with the U.S. Food and Drug Administration.
Amgen's 2009 sales of Epogen totaled $2.6 billion, while J&J's Procrit sales were $2.2 billion over the same period.
Both medicines are engineered antibodies that work by stimulating production of red blood cells.
http://www.reuters.com/article/idUSTRE68N2WB20100924
By Deena Beasley
LOS ANGELES Fri Sep 24, 2010 2:09pm EDT
LOS ANGELES (Reuters) - Amgen Inc is recalling several hundred lots of anemia drugs Epogen and Procrit, sold by Johnson & Johnson, because vials of the injectable medicines might develop tiny glass flakes that could cause blood clots and other serious health problems.
Amgen, which sells Epogen, manufactures the identical drugs at a plant in Puerto Rico.
Amgen spokeswoman Emma Hurley said the recall, which included 200 lots of Epogen, is not expected to disrupt availability of the drug and the biotechnology company does not expect a material financial impact.
J&J spokeswoman Lisa Vaga said 155 lots of Procrit were recalled, but declined to comment on any financial impact to the company.
Amgen said there have been no patient complaints that can be directly attributed to the presence of glass. It said the lots were being voluntarily recalled as a precaution.
The glass flakes result from the interaction of the drug with glass vials over the shelf life of the product, the company said.
Hurley said expiration dates for the drugs have been reduced to 12 months for single-dose vials and 15 months for multi-dose vials. Their shelf life had been 36 months.
She also said the company would switch vial manufacturers.
"From an investor standpoint, I don't think there's any real impact at all," said Cowen & Co analyst Eric Schmidt. "There's no patient safety issue, no one's been harmed here. There's no supply issue. There will be plenty of supply to go around."
Amgen sells Epogen in the United States, where it is used mostly for kidney dialysis patients. Under a long-standing license from Amgen, J&J's Centocor Ortho Biotech unit distributes Procrit in the United States, mainly for cancer and HIV patients. J&J has been dealing with a rash of recalls of its consumer medicines.
Biotechnology company Genzyme Corp has had its reputation damaged by product shortages caused by manufacturing quality control issues.
Since the Amgen recall relates to materials rather than production processes, the impact on the company will be much more limited, said Bernstein & Co analyst Geoffrey Porges.
Amgen said the recall is being conducted in cooperation with the U.S. Food and Drug Administration.
Amgen's 2009 sales of Epogen totaled $2.6 billion, while J&J's Procrit sales were $2.2 billion over the same period.
Both medicines are engineered antibodies that work by stimulating production of red blood cells.
http://www.reuters.com/article/idUSTRE68N2WB20100924
Video/Telaprevir
Matthew Emmens, chief executive officer of Vertex Pharmaceuticals Inc., talks with Bloomberg's Julie Hyman about the outlook for the company's experimental hepatitis C treatment, in development with Johnson & Johnson, called telaprevir.
k
A study found that telaprevir worked in patients with hepatitis C who didn’t respond to other treatment. No proven medicines are available for hepatitis C patients who don’t respond to standard care.
k
(Source: Bloomberg)
Sept. 8 (Bloomberg) --http://www.clipsyndicate.com/video/play/1682082
Hepatic encephalopathy
Pharmacotherapy for hepatic encephalopathy.
Phongsamran PV, Kim JW, Cupo Abbott J, Rosenblatt A.
Department of Clinical Pharmacy, University of Southern California School of Pharmacy, USC University Hospital Department of Pharmacy, Los Angeles, California, USA. phongsam@usc.edu
Abstract
Hepatic encephalopathy (HE) is a challenging clinical complication of liver dysfunction with a wide spectrum of neuropsychiatric abnormalities that range from mild disturbances in cognitive function and consciousness to coma and death. The pathogenesis of HE in cirrhosis is complex and multifactorial, but a key role is thought to be played by circulating gut-derived toxins of the nitrogenous compounds, most notably ammonia.
Therapeutic treatment options for HE are currently limited and have appreciable risks and benefits associated with their use. Management of HE primarily involves avoidance of precipitating factors, limitation of dietary protein intake, and administration of various ammonia-lowering therapies such as non-absorbable disaccharides and select antimicrobial agents. Non-absorbable disaccharides, such as lactulose, have traditionally been regarded as first-line pharmacotherapy for patients with HE.
However, multiple adverse events have been associated with their use. In addition, recent literature has questioned the true efficacy of the disaccharides for this indication. Neomycin, metronidazole and vancomycin may be used as alternative treatments for patients intolerant or unresponsive to non-absorbable disaccharides. Antimicrobials reduce bacterial production of ammonia and other bacteria-derived toxins through suppression of intestinal flora. Neomycin has been reported to be as effective as lactulose, and similar efficacy has been reported with vancomycin and metronidazole for the management of HE.
However, the adverse effects frequently associated with these antimicrobials limit their use as first-line pharmacological agents. Neomycin is the most commonly used antimicrobial for HE and, although poorly absorbed, systemic exposure to the drug in sufficient amounts causes hearing loss and renal toxicity. Long-term neomycin therapy requires annual auditory testing and continuous monitoring of renal function. Long-term use of metronidazole has been associated with neurotoxicity in patients with cirrhosis, including dose-dependent peripheral neuropathy. Vancomycin may be a safer option for HE in patients with chronic liver disease; however, limited experience, possible bacterial overgrowth and risk for enteric bacteria resistance preclude the routine use of vancomycin for HE. Rifaximin is a novel antimicrobial agent with a wide spectrum of activity that has shown promise as an alternative antimicrobial treatment option for HE. Several clinical trials have compared rifaximin to the disaccharides, lactulose and lactitol, and the antimicrobial neomycin. Rifaximin appears to be at least as effective as conventional drug therapy and has been associated with fewer adverse effects due to its limited systemic absorption. The available clinical data appear to support a favourable benefit-risk ratio for rifaximin, which has shown efficacy with an improved tolerability profile.
Future studies are needed in order to truly characterize its cost effectiveness in today's healthcare environment. Other less frequently utilized alternative treatment options include administration of benzodiazepine receptor antagonists, branched-chain amino acids, ornithine aspartate, zinc supplementation, sodium benzoate, dopamine receptor agonists, acarbose and probiotics. Presently, there is relatively limited clinical data supporting their routine use in HE.
Drugs. 2010 Jun 18;70(9):1131-48. doi: 10.2165/10898630-000000000-00000.
PMID: 20518580 [PubMed - indexed for MEDLINE]
Source
Phongsamran PV, Kim JW, Cupo Abbott J, Rosenblatt A.
Department of Clinical Pharmacy, University of Southern California School of Pharmacy, USC University Hospital Department of Pharmacy, Los Angeles, California, USA. phongsam@usc.edu
Abstract
Hepatic encephalopathy (HE) is a challenging clinical complication of liver dysfunction with a wide spectrum of neuropsychiatric abnormalities that range from mild disturbances in cognitive function and consciousness to coma and death. The pathogenesis of HE in cirrhosis is complex and multifactorial, but a key role is thought to be played by circulating gut-derived toxins of the nitrogenous compounds, most notably ammonia.
Therapeutic treatment options for HE are currently limited and have appreciable risks and benefits associated with their use. Management of HE primarily involves avoidance of precipitating factors, limitation of dietary protein intake, and administration of various ammonia-lowering therapies such as non-absorbable disaccharides and select antimicrobial agents. Non-absorbable disaccharides, such as lactulose, have traditionally been regarded as first-line pharmacotherapy for patients with HE.
However, multiple adverse events have been associated with their use. In addition, recent literature has questioned the true efficacy of the disaccharides for this indication. Neomycin, metronidazole and vancomycin may be used as alternative treatments for patients intolerant or unresponsive to non-absorbable disaccharides. Antimicrobials reduce bacterial production of ammonia and other bacteria-derived toxins through suppression of intestinal flora. Neomycin has been reported to be as effective as lactulose, and similar efficacy has been reported with vancomycin and metronidazole for the management of HE.
However, the adverse effects frequently associated with these antimicrobials limit their use as first-line pharmacological agents. Neomycin is the most commonly used antimicrobial for HE and, although poorly absorbed, systemic exposure to the drug in sufficient amounts causes hearing loss and renal toxicity. Long-term neomycin therapy requires annual auditory testing and continuous monitoring of renal function. Long-term use of metronidazole has been associated with neurotoxicity in patients with cirrhosis, including dose-dependent peripheral neuropathy. Vancomycin may be a safer option for HE in patients with chronic liver disease; however, limited experience, possible bacterial overgrowth and risk for enteric bacteria resistance preclude the routine use of vancomycin for HE. Rifaximin is a novel antimicrobial agent with a wide spectrum of activity that has shown promise as an alternative antimicrobial treatment option for HE. Several clinical trials have compared rifaximin to the disaccharides, lactulose and lactitol, and the antimicrobial neomycin. Rifaximin appears to be at least as effective as conventional drug therapy and has been associated with fewer adverse effects due to its limited systemic absorption. The available clinical data appear to support a favourable benefit-risk ratio for rifaximin, which has shown efficacy with an improved tolerability profile.
Future studies are needed in order to truly characterize its cost effectiveness in today's healthcare environment. Other less frequently utilized alternative treatment options include administration of benzodiazepine receptor antagonists, branched-chain amino acids, ornithine aspartate, zinc supplementation, sodium benzoate, dopamine receptor agonists, acarbose and probiotics. Presently, there is relatively limited clinical data supporting their routine use in HE.
Drugs. 2010 Jun 18;70(9):1131-48. doi: 10.2165/10898630-000000000-00000.
PMID: 20518580 [PubMed - indexed for MEDLINE]
Source
Long-Term Entecavir Therapy Reverses Fibrosis and Cirrhosis
Long-Term Entecavir Therapy Reverses Fibrosis and Cirrhosis in Patients With Chronic Hepatitis B
l
Fran Lowry
August 25, 2010 — Long-term antiviral therapy for 3 years or more with entecavir reverses fibrosis and cirrhosis in patients with chronic hepatitis B virus (HBV) infection, according to a new study published online August 3 in Hepatology.
"Chronic hepatitis B (CHB) infection affects over 350 million people worldwide," write Ting-Tsung Chang, MD, from National Cheng Kung University Medical College, Tainan, Taiwan, and colleagues. "Viral replication is now recognized as the key driver of liver injury and disease progression, and thus the primary aim of treatment for chronic HBV infection is long-term suppression of HBV replication to undetectable levels."
Previous studies showed that continuous treatment with entecavir for periods ranging from 48 weeks to 3 years resulted in potent virologic suppression and improvement in virologic, histologic, and biochemical outcomes in nucleoside-naive patients, with minimal emergence of resistance.
The aim of the present study was to determine if long-term entecavir treatment continued to provide histologic improvement and reversal of fibrosis or cirrhosis in patients with chronic HBV infection.
The researchers evaluated nucleoside-naive patients from two phase 3 studies with entecavir who subsequently entered an open-label rollover study and received entecavir for a total duration of at least 3 years. During the phase 3 trials, patients received entecavir 0.5 mg daily, and during the long-term rollover study, they received 1.0 mg of entecavir daily. In addition, some patients received concurrent lamivudine 100 mg daily for a brief period early in the rollover study before continuing with entecavir monotherapy after the study protocol was amended.
The 69 patients, 50 of whom tested positive for hepatitis B e antigen (HBeAg) and 19 who tested negative for HBeAg, underwent long-term liver biopsies. The median time of liver biopsy was 6 years (range, 3 - 7 years).
The investigators analyzed histologic improvement in 57 patients who had an adequate baseline biopsy, an adequate long-term biopsy, and a baseline Knodell necroinflammatory score of 2 or greater.
At the time of the long-term biopsy, all patients had HBV DNA levels of less than 300 copies/mL, and 86% had normalized alanine aminotransferase (ALT) levels.
Histologic improvement, defined as a decrease of 2 points or greater in the Knodell necroinflammatory score and no worsening of the Knodell fibrosis score, was observed in 96% of patients. In addition, an improvement of more than 1 point in the Ishak fibrosis score was seen in 88%, including all 10 patients who had advanced fibrosis or cirrhosis when they entered the phase 3 studies, the authors report.
Most patients (96%) experienced at least 1 adverse event at some time during entecavir treatment. Serious adverse events occurred in 25% of patients. No patient stopped entecavir because of adverse events.
The authors point out their study limitations, which include changes to the long-term rollover study, which made it impossible to evaluate the effect of the increased dose of entecavir or concurrent lamivudine on the results.
"These data support the conclusion that in most nucleoside-naïve patients, long-term entecavir therapy leads to potent suppression of HBV DNA, normalization of ALT and improvement in liver histology with accompanying regression of fibrosis, including those with advanced fibrosis or cirrhosis at baseline," the study authors conclude. "Substantially more patients demonstrated histologic improvement at the time of the long-term biopsy compared to week 48, confirming the value of long-term treatment for chronic HBV infection. The safety profile, potent suppression of HBV replication, and low potential for antiviral drug resistance in nucleoside-naïve patients make long-term treatment of CHB with entecavir monotherapy possible."
Commentary: Study Supports Past Findings
Asked to provide independent commentary about this study by Medscape Medical News, Kapil Chopra, MD, clinical director of hepatology at the University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, said the study was able to demonstrate clearly that long-term antiviral therapy with entecavir improves the inflammation and reverses the fibrosis that occurs with chronic HBV infection.
"The study supports the earlier observations that effectively suppressing hepatitis B viral replication provides tangible, histologic benefits. If the virus can be adequately suppressed or made undetectable by antiviral therapy, then these benefits are much more likely," he said. "It tells us that the longer the duration of antiviral therapy the more benefit in terms of reversing the damage caused by the virus."
Dr. Chopra added that the level of resistance to entecavir was low. "This is the first time that a potent drug like entecavir has shown such a very low level of resistance, unlike that seen with lamivudine and adefovir. The sustained benefit is lost if resistance develops during antiviral therapy, so if you can avoid resistance, there is more likelihood of long-term benefit."
That some patients also received concurrent treatment with lamivudine "makes it difficult to draw conclusions that monotherapy with entecavir alone leads to these good outcomes. And in patients with cirrhosis, there is a sampling error using histology alone. A more solid endpoint would have been improvement in portal pressure, but this was not used here," Dr. Chopra said.
He added that it remains unclear whether the good results seen with long-term entecavir therapy will lead to any change in the incidence of hepatocellular carcinoma.
The study was sponsored by Bristol-Myers Squibb Pharmaceutical Research Institute. Dr. Chang has disclosed various financial relationships with Gilead Sciences, Bristol-Myers Squibb Co, GlaxoSmithKline, Schering-Plough Corp, and Pfizer Inc. Dr. Chopra has disclosed no relevant financial relationships.
Hepatology. Published online August 3, 2010. Abstract
Fran Lowry
August 25, 2010 — Long-term antiviral therapy for 3 years or more with entecavir reverses fibrosis and cirrhosis in patients with chronic hepatitis B virus (HBV) infection, according to a new study published online August 3 in Hepatology.
"Chronic hepatitis B (CHB) infection affects over 350 million people worldwide," write Ting-Tsung Chang, MD, from National Cheng Kung University Medical College, Tainan, Taiwan, and colleagues. "Viral replication is now recognized as the key driver of liver injury and disease progression, and thus the primary aim of treatment for chronic HBV infection is long-term suppression of HBV replication to undetectable levels."
Previous studies showed that continuous treatment with entecavir for periods ranging from 48 weeks to 3 years resulted in potent virologic suppression and improvement in virologic, histologic, and biochemical outcomes in nucleoside-naive patients, with minimal emergence of resistance.
The aim of the present study was to determine if long-term entecavir treatment continued to provide histologic improvement and reversal of fibrosis or cirrhosis in patients with chronic HBV infection.
The researchers evaluated nucleoside-naive patients from two phase 3 studies with entecavir who subsequently entered an open-label rollover study and received entecavir for a total duration of at least 3 years. During the phase 3 trials, patients received entecavir 0.5 mg daily, and during the long-term rollover study, they received 1.0 mg of entecavir daily. In addition, some patients received concurrent lamivudine 100 mg daily for a brief period early in the rollover study before continuing with entecavir monotherapy after the study protocol was amended.
The 69 patients, 50 of whom tested positive for hepatitis B e antigen (HBeAg) and 19 who tested negative for HBeAg, underwent long-term liver biopsies. The median time of liver biopsy was 6 years (range, 3 - 7 years).
The investigators analyzed histologic improvement in 57 patients who had an adequate baseline biopsy, an adequate long-term biopsy, and a baseline Knodell necroinflammatory score of 2 or greater.
At the time of the long-term biopsy, all patients had HBV DNA levels of less than 300 copies/mL, and 86% had normalized alanine aminotransferase (ALT) levels.
Histologic improvement, defined as a decrease of 2 points or greater in the Knodell necroinflammatory score and no worsening of the Knodell fibrosis score, was observed in 96% of patients. In addition, an improvement of more than 1 point in the Ishak fibrosis score was seen in 88%, including all 10 patients who had advanced fibrosis or cirrhosis when they entered the phase 3 studies, the authors report.
Most patients (96%) experienced at least 1 adverse event at some time during entecavir treatment. Serious adverse events occurred in 25% of patients. No patient stopped entecavir because of adverse events.
The authors point out their study limitations, which include changes to the long-term rollover study, which made it impossible to evaluate the effect of the increased dose of entecavir or concurrent lamivudine on the results.
"These data support the conclusion that in most nucleoside-naïve patients, long-term entecavir therapy leads to potent suppression of HBV DNA, normalization of ALT and improvement in liver histology with accompanying regression of fibrosis, including those with advanced fibrosis or cirrhosis at baseline," the study authors conclude. "Substantially more patients demonstrated histologic improvement at the time of the long-term biopsy compared to week 48, confirming the value of long-term treatment for chronic HBV infection. The safety profile, potent suppression of HBV replication, and low potential for antiviral drug resistance in nucleoside-naïve patients make long-term treatment of CHB with entecavir monotherapy possible."
Commentary: Study Supports Past Findings
Asked to provide independent commentary about this study by Medscape Medical News, Kapil Chopra, MD, clinical director of hepatology at the University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, said the study was able to demonstrate clearly that long-term antiviral therapy with entecavir improves the inflammation and reverses the fibrosis that occurs with chronic HBV infection.
"The study supports the earlier observations that effectively suppressing hepatitis B viral replication provides tangible, histologic benefits. If the virus can be adequately suppressed or made undetectable by antiviral therapy, then these benefits are much more likely," he said. "It tells us that the longer the duration of antiviral therapy the more benefit in terms of reversing the damage caused by the virus."
Dr. Chopra added that the level of resistance to entecavir was low. "This is the first time that a potent drug like entecavir has shown such a very low level of resistance, unlike that seen with lamivudine and adefovir. The sustained benefit is lost if resistance develops during antiviral therapy, so if you can avoid resistance, there is more likelihood of long-term benefit."
That some patients also received concurrent treatment with lamivudine "makes it difficult to draw conclusions that monotherapy with entecavir alone leads to these good outcomes. And in patients with cirrhosis, there is a sampling error using histology alone. A more solid endpoint would have been improvement in portal pressure, but this was not used here," Dr. Chopra said.
He added that it remains unclear whether the good results seen with long-term entecavir therapy will lead to any change in the incidence of hepatocellular carcinoma.
The study was sponsored by Bristol-Myers Squibb Pharmaceutical Research Institute. Dr. Chang has disclosed various financial relationships with Gilead Sciences, Bristol-Myers Squibb Co, GlaxoSmithKline, Schering-Plough Corp, and Pfizer Inc. Dr. Chopra has disclosed no relevant financial relationships.
Hepatology. Published online August 3, 2010. Abstract
SUPERBUGS & INFECTIOUS DISEASE
Superbugs & Infectious Disease
Amber Dance(Los Angeles Times, September 27, 2010)"Doctors and infectious bacteria are locked in an arms race. In this ever-escalating battle, the bacteria evolve ways to avoid every drug humans throw at them. The conflict has intensified lately as more and more bacteria -- particularly those lurking in hospitals -- become able to resist nearly every antibiotic in our arsenal. 'We throw thousands and thousands of antibiotics on bacteria,' says Marcin Filutowicz, a microbiologist at the University of Wisconsin in Madison. 'This is tremendous selection for antibiotic-resistant bacteria.' The situation is forcing scientists to think creatively about where the next antibacterial medications will come from and how they will work. Here are five provocative ideas."Free registration required.
Arthur Allen(The Washington Post, September 27, 2010)"[Whooping cough] is staging a comeback in California, in what public health officials worry could be a harbinger of a national trend…CDC officials say the California epidemic could herald a wider spread and are recommending that parents make sure their kids are vaccinated. Last week, officials in Indiana and South Carolina said they were seeing an upsurge of the disease. Before 2005, there was no persussis-containing vaccine for anyone older than 6. Since then, booster vaccines have been licensed, and most jurisdictions, including Maryland, Virginia and the District, require adolescents to get a booster by age 12. Public health authorities are urging adults to get boosters, too, especially hospital employees, new mothers and others in contact with vulnerable infants."Free registration required.
OpinionWendy Orent, author who specializes in infectious disease issues(Los Angeles Times, September 26, 2010)"Most vertebrate animal species have some sort of poxvirus capable of causing severe illness. These ancient pathogens have evolved within and among vertebrates since the dawn of life. In one of public health's greatest triumphs…smallpox…was eradicated by 1980…Now, however, some researchers are concerned that another orthopox virus, monkeypox, may be adapting to fill the void. Currently, monkeypox can spread to humans fairly easily if they come into contact with an infected animal. It doesn't always spread from human to human. But that could change…Researchers are united in their insistence that surveillance in the Congo is crucial, no matter how difficult it is to access the remote places haunted by monkeypox."Free registration required.
Antiviral therapy in HCV-infected decompensated cirrhotics
What is decompensated cirrhosis?
If you experience any of the serious problems described below, your disease has progressed from compensated cirrhosis to decompensated cirrhosis.
.
Bleeding varices (internal bleeding)
Ascites (fluid in the belly)
Encephalopathy (confusion)
Jaundice (yellowing of eyes and skin)
Ascites (fluid in the belly)
Encephalopathy (confusion)
Jaundice (yellowing of eyes and skin)
.
Management of the Decompensated Cirrhotic Patient with HCV
Sakib K. Khalid, M.D.Guadalupe Garcia-Tsao. M.D
(To see the figures and illustrations in this article, please download the pdf version.)
Sakib K. Khalid, M.D.Guadalupe Garcia-Tsao. M.D
(To see the figures and illustrations in this article, please download the pdf version.)
K
Antiviral therapy in HCV-infected decompensated cirrhotics
.
Saudi J Gastroenterol Year : 2010 Volume : 16 Issue : 4 Page : 310-314
Fazal A Danish 1, Salman S Koul 2, Fazal R Subhani 3, Ahmed E Rabbani 4, Saeeda Yasmin 5
1 St Mary's Hospital, Isle of Wight, PO30 5TG, United Kingdom
2 Department of Medicine, Pakistan Institute of Medical Sciences (PIMS), Islamabad, Pakistan
3 Department of Pediatrics, Holy Family Hospital, Rawalpindi, Pakistan
4 Foundation University Medical College (FUMC), Rawalpindi, Pakistan
5 Department of Surgery, Shifa International Hospital, Islamabad, Pakistan
Click here for correspondence address and email
Date of Submission 01-Sep-2009
Date of Acceptance 05-Mar-2010
Date of Web Publication 24-Sep-2010
Abstract
Decompensated cirrhosis has traditionally been considered a contraindication to interferon and ribavirin therapy. Whereas, the same may be true for advanced cirrhosis, which is only successfully amenable to liver transplantation (LT), there are reports in the literature in which antiviral therapy was given successfully in selected cases of early hepatic decompensation with an aim to attain sustained viral clearance, halt disease progression, and expect potential (though, often, partial) recovery of hepatic metabolic activity. Antiviral therapy may also be instituted to prevent hepatitis C recurrence after LT (it has even caused removal of some patients from the waiting list for LT). Thus, decompensation per se is no more an absolute contraindication to antiviral therapy. Nonetheless, considering that a large proportion of such patients have pre-existing hematological cytopenias, modifications in antiviral dose regimens and close monitoring is required in order to prevent worsening of the same. Although the final sustained virological response rates attained in these patients are relatively low, successful antiviral therapy is potentially lifesaving which explains the need to go for it. In this article, the pros and cons of antiviral therapy in decompensated liver cirrhosis are reviewed with special emphasis on how to avoid antiviral dose reductions/withdrawals secondary to the development of hematologic side effects by using hematopoietic growth factors.
Keywords: Antiviral therapy, chronic hepatitis C, decompensated cirrhosis, hematopoietic growth factors
Whereas, decompensated cirrhosis of liver has traditionally been considered a contraindication to antiviral therapy, the same is not true anymore. Ribavirin-induced hemolytic anemia and interferon-induced neutropenia are one of the most common causes of antiviral dose reductions/withdrawal, particularly in decompensated cirrhotics. Although, no consensus still exists, there are some recent reports in the literature that suggest the use of hematopoietic growth factors (HGF's) in selected cases of hemolytic anemia and neutropenia. Whereas, the addition of growth factors substantially increases the overall cost of the treatment, the same have provided an opportunity to institute antiviral therapy in some of the conditions previously included in the list of contraindications to antiviral therapy (like decompensated cirrhosis). Although more studies are needed to truly define the indications, dose regimen, side effects, and therapeutic efficacy of these factors, the initial results are encouraging and hematopoietic growth factors appear to be a useful adjunct to the antiviral therapy.
Fibrosis is the histopathological hallmark of chronic hepatitis causing progressive derangement of normal liver architecture with consequent reduction in hepatic synthetic function. Chronic liver disease is said to be decompensated when one or the other complication of chronic liver disease has developed - ascites, variceal bleeding (secondary to portal hypertension), impaired hepatic synthetic function (hypoalbuminemia), jaundice, or hepatic encephalopathy. Five year survival rate in decompensated cirrhotics is estimated to be 50%. [1] Liver transplantation (LT) is the treatment of choice in all such cases. If hepatitis C virus (HCV) is not eradicated before going for LT, reinfection with HCV occurs in all transplant recipients as a rule. This in turn leads to cirrhosis in around 30% patients in 5 years. [2] It is thus very common to see progressive post-transplantation disease of the allograft in HCV-infected cases. Pre-transplantation HCV eradication is associated with less likelihood of reinfection and this forms the rationale for treating decompensated cirrhotics waiting LT with antiviral therapy; [3] initiating pre-emptive post-transplantation antiviral therapy, and treating established post-transplant chronic hepatitis being other therapeutic options in cirrhotics.
LT per se is not a practical option for a great majority of the cirrhotic patients. This is not only because of limited number of organ donors available at a given time, but also because of the age-related cardiovascular, renal and/or pulmonary derangements that practically make going for LT infeasible and at times rather irrational. Additionally, old age (≥65 years) is generally considered an exclusion criterion for LT. In a nutshell, exploring and offering some potentially successful treatment option (like antiviral therapy) is the need of the hour in cirrhotics.
The aim of instituting pre-transplantation antiviral therapy is either to attain a SVR at transplantation, or an on-treatment HCV RNA clearance at transplantation. Importantly, mere reduction of viral load should not be the aim because, unlike HBV cirrhotics, this has not been shown to decrease the rate and/or severity of recurrence in HCV cases.
Traditionally, despite the known theoretical benefits of antiviral therapy (improvement in liver histology, partial reversal of established cirrhosis, and prevention of life-threatening complications), many cirrhotic patients have not been offered antiviral therapy. Peginterferon-ribavirin combination therapy has limited efficacy in patients with decompensated cirrhosis. [4],[5] Also, antiviral therapy is not safe from potentially serious adverse effects in this population group. As decompensated cirrhotics are more prone to develop hematologic side effects (neutropenia, thrombocytopenia and anemia) with antiviral therapy as compared to non-cirrhotics, [6] patients who already have neutropenia or thrombocytopenia below the permissible limits (neutrophil count >1500/mm 3 ; thrombocyte count >75,000/mm 3 ) are highly prone to develop life-threatening infections after starting antiviral therapy, particularly if they have Child-Pugh class C disease. [7],[8] Also, it is generally thought that age-related derangements in cardiovascular and pulmonary functions make the cirrhotic patients less tolerant to ribavirin-induced hemolytic anemia. Finally, there are concerns regarding decompensation actually made worse by antiviral therapy as is the case with decompensated chronic hepatitis B cases [9] (if you can't do any good to the patient, at least don't harm him, policy!).
The current literature review, however, shows that because of the unstandardized dosage schedules being administered over variable periods of time in the past studies, we have under- and overestimated the potential benefits and risks of antiviral therapy respectively in decompensated cirrhotic patients. There are now several reports in the literature in which antiviral therapy was relatively well tolerated in decompensated cirrhotic patients with reasonable attainment of ETR and SVR rates. [4],[7],[10],[11] In one study, [7] 39% of the patients receiving low, accelerating regimen of non-pegylated interferon plus ribavirin experienced clearance of HCV-RNA, and 21% attained an SVR. Results with pegylated interferon are even better. In the first study [12] proving the benefits of antiviral therapy in cirrhotics with signs of portal hypertension, 51 cirrhotics received 1 mg/kg/week of pegylated-interferon a-2b plus oral ribavirin at a fixed dose of 800 mg/day for 52 weeks. By intention-to-treat analysis, SVR was achieved in 21.6% patients. As otherwise, patients with genotypes 2 and 3 showed better results (83.3%) than genotype 1 cases (13.3%). Although antiviral therapy was stopped in five of the patients because of neutrophil counts falling below 0.75Χ10 3 /dL, none of them developed superadded infections. The disease deteriorated in only 6% of those who attained SVR compared to 38% of the non-responders. In another study, [10] Peg-IFN α-2b (1.0 mg/kg) plus standard dose of ribavirin were administered to all patients for 24 weeks regardless of the genotype. The overall SVR rate attained even with this suboptimal dose regimen was 19.7%. Except patients with very advanced liver disease (CTP score >10), none experienced life-threatening complications. Peg-IFN and ribavirin in the standard dosage (Peg-IFN α-2b 1.5 mg/kg and ribavirin 800-1000 mg for genotypes 2 and 3, and 1000-1200 mg for genotypes 1 and 4) for the standard duration of time (48 and 24 weeks for genotype 1 and non-1, respectively) have also been tried. In one study, [13] 35% of end-staged cirrhotics cleared the HCV infection (16% genotype 1 and 4, and 59% genotype 2 and 3 cases). 60% of all patients tolerated this 'standard' treatment without any major untoward effect; treatment was discontinued in 19.1% of the patients with 4 among those ending up having severe superadded infections. In yet another study, [14] a 48 week course was planned for patients who demonstrate EVR with a standard regimen of PEG-IFN alfa-2a (135μg, once a week) plus ribavirin (1000-1200 mg/day). Results showed 60% patients completing the course, with ETR and SVR achieved in 45% and 35% cases respectively. In a recent study, [15] aimed to evaluate both the prevention of post-transplantation HCV recurrence and the risk of bacterial infections during therapy, 47% patients achieved HCV RNA negativity during treatment, 29% were HCV RNA negative at the time of transplantation (drop outs n=3, deaths n=4, viral relapse n=2), and 20% achieved an SVR post-transplantation. Importantly, none of the patients who achieved SVR pre-transplantation developed a recurrence post-transplantation.
Based on the current literature review it is suggested that all cirrhotic patients with a CTP score ≤9 and history of a decompensated event that abated with routine therapy be offered antiviral therapy. A suggested protocol could be Peg-IFN α-2b in a dose of 1.5 mg/kg and ribavirin in a dose of 800-1000 mg for genotypes 2 and 3, and 1000-1200 mg for genotypes 1 and 4 for 48 and 24 weeks for genotype 1 and non-1, respectively. As otherwise, attainment of a rapid / early virological response and genotypes 2 and 3 are the most robust predictors of viral clearance with antiviral therapy. [10],[12] Child-Pugh score class A (in genotype 1 cases only) and lower pre-transplantation viral loads are other positive predictors. A reduction in the viral load of ≤2 log 10 between baseline and week 4, and baseline Child-Pugh score of C or MELD >18 have a strong negative predictive value. In the absence of a ≥2 log 10 reduction in HCV RNA at week 4, probably the best approach to reduce the risk of complications is to stop antiviral therapy at this point.
As a general rule, decompensated cirrhotics are more prone to develop drug-induced side-effects compared to patients with compensated disease. Drug-induced neutropenia, thrombocytopenia, anemia, superadded infections (SBP etc), and liver decompensation during therapy are reported to occur in 50-60%, 30-50%, 30-60%, 4-13%, and 11-20% of decompensated cirrhotic cases respectively. [4],[10],[12] In one study, [16] the relative frequencies of clinical decompensation (22% vs. 18%, p0 =0.62), death before LT (8% vs. 2% p0 =0.06) or 24 weeks after LT (8% vs. 12%; p0 =0.67) were similar in treated and control subjects. However, a significantly higher incidence of superadded infections (spontaneous bacterial peritonitis and spontaneous bacteremia due to Gram-negative bacilli) was noted in the treated subjects (25%) compared to the controls (6%) ( p0 =0.01). Septic shock developed in 10% of the treated subjects compared to none in the control arm ( p0 =0.05). Studies have demonstrated that, besides antiviral therapy, variables independently associated with higher incidence of infective episodes include Child-Pugh class C (score of 12 (±1.2) and a neutrophil count <900>4 g/dL, Hb levels of <8>11 g/dL (return to the pretreatment level is not the aim). [23] Another study suggested starting EPO therapy at a lower dose of 4,000 IU SQ thrice weekly (12,000 IU/week) and then increasing the dose depending upon the response. [24] The first evidence of a response to the thrice weekly EPO administration is an increase in the reticulocyte count within 10 days. [25] Since erythroid progenitors take several days to mature, a clinically significant increase in hematocrit is usually not observed in less than 2 weeks and may require up to 6 weeks in some patients. [26] If the rate of rise of hemoglobin is greater than 1 g/dL over 2 weeks, it generally warrants decreasing EPO dose. This is because a greater than 1 g/dL rise in any 2 weeks during the course of the therapy has been associated with an increased risk of thromboembolic phenomenon, predisposing to myocardial infarction, stoke and even death. [27] Also, according to manufacturer's recommendations, a Hb level of greater than 12 g/dL should not be aimed, the reason being potentially increased risk of thromboembolic phenomenon. [28] Once adequate Hb level (≥10 g/dL) is achieved, ribavirin dose can be increased to the optimum level. [20] Once started, adjunct EPO therapy may be required till the very end of the treatment. In one study, [24] the median duration of EPO treatment was 24 weeks (range 6-39).
Regarding G-CSF, the current recommendation [21] is to reduce IFN dose if neutrophil count falls to <0.5 Χ 1 0 9 /L, and discontinue it if it falls to <0.3 Χ 10 9 /L. [17] Regarding platelet count, IFN dose should be reduced if platelet count falls to <30 Χ 10 9 /L, and discontinued if it falls to <20 Χ 10 9 /L. [17] The minimum effective dose of pegylated interferon appears to be 1 μg/kg/week. If despite of reducing the pegylated interferon dose to the minimum effective level, neutrophil counts of <0.5 Χ 10 9 /L and platelet counts of <30 Χ 10 9 /L persist, instituting G-CSF therapy may be considered. [21]
A suggested dose regimen is to start G-CSF therapy at a dose of 30 MU SQ once weekly and then to adjust it as per the response/requirement. Complete blood counts should be asked twice or thrice weekly and response to therapy monitored. Once adequate neutrophil count is achieved, IFN dose can be increased to the optimum level. [21] Once started, adjunct G-CSF therapy may be required till the end of the treatment. In one study, [24] the median duration of G-CSF therapy was 20 weeks (range 9-45).
Although it is not yet clear how much survival benefit antiviral therapy confers, a standardized mortality rate analysis in one study reported a lower liver-related mortality among cirrhotics with SVR (0.6: CI: 0.0-3.1) compared to untreated patients. [29] In post-liver transplant cases, avoidance of allograft failure due to recurrence of HCV infection has also been reported in the literature although it needs further study and validation. [30]
Conclusion
Although, decompensated cirrhosis of liver is no more considered an absolute contraindication to interferon therapy, because of the high risk of septic complications and low probability of attainment of an SVR, patients with Child-Pugh class C, CTP score ≥10 or MELD score 18 disease are not considered appropriate candidates for antiviral therapy. The ideal candidate for antiviral therapy remains a patient with Child-Pugh class A disease in whom the risk of drug-induced side effects is almost identical to that of the controls. Whether or not to institute antiviral therapy in Child-Pugh class B, patients should be individualized on case-to-case basis giving due consideration to factors like genotype and pre-treatment viral loads with antiviral therapy discontinued after 4 or 12 weeks if there is no virological response. Standard schedules of treatment may be considered in all patients with genotype 2 and 3 HCV infection; in genotype 1 cases, however, the risk-benefit ratio still needs to be defined. All cirrhotic patients on antiviral therapy need adjustment of the dosage schedule in accordance with the tolerability of the patient, especially in response to the development of hematologic side effects. HGF's, though not routinely recommended, appear to be a useful adjunct to antiviral therapy to reduce antiviral dose reductions/withdrawal. Since, addition of HGF's substantially increases the overall cost of the therapy, more studies are needed to establish the lower cut off limits for different blood counts below which HGF therapy may be considered. Additionally, norfloxacin prophylaxis has been shown to substantially reduce the risk of superadded infections. One thing that has increasingly become clear from the existing trial's data is that cirrhotic patients who achieve SVR are less likely to develop liver-related complications as compared to the non-responders. Despite the many encouraging studies in the recent past, however, data on the long-term disease progression, avoidance of transplantation, and most importantly, improvement of life expectancy are still sparse. Although liver functions have clearly been shown to improve with antiviral therapy (as indicated by significant reductions in CTP and MELD scores), the same are more likely to deteriorate within a few years in patients with advanced cirrhosis thus explaining the need to accumulate data on the survival benefit conferred by antiviral therapy in cirrhotic patients. Although not yet tried, novel therapeutic strategies like direct antiviral agents are likely to be most beneficial in patients with decompensated disease.
References
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