Hello folks,Its a cold snowy day here in Michigan, hope its warmer in your part of the world
Welcome to HCV rewind, a weekly digest of news, research and a look at today's headlines.
Interferon Free
Published recently online at Medscape, is a look into the therapeutic options beyond interferon for the treatment of hepatitis C, presented by Catherine AM Stedman.
Current Prospects for Interferon-free Treatment of Hepatitis C in 2012
Published Jan 22 2013 in Journal of Gastroenterology and Hepatology
Numerous other DAAs are in clinical development, and phases 2 and 3 trials are evaluating interferon-free combination DAA therapy.
Interferon-free sustained virologic responses have now been achieved with combinations of asunaprevir and daclatasvir; sofosbuvir and ribavirin; sofosbuvir and daclatasvir; faldaprevir and BI207127; ABT-450, ritonovir and ABT-333; ABT-450, ritonovir and ABT-072; miracitabine, danoprevir and ritonavir; and alisporivir and ribavirin.
Some drugs are genotype-specific in their activity, whereas others are pan-genotypic, and differential responses for the genotype 1 subtypes 1a and 1b have emerged with many DAA combinations. Viral breakthrough and resistance are important considerations for future trial design. The prospect of interferon-free combination DAA therapy for hepatitis C virus is now finally becoming a reality.
Continue reading at Medscape or here on the blog.
Updates Telaprevir
Futility rules defined for telaprevir-based HCV therapy
Therapy with telaprevir, peginterferon, and ribavirin should be stopped in both treatment-naive and treatment-experienced patients with hepatitis C virus infection if HCV RNA levels are greater than 1,000 IU/mL at week 4 or 12 of treatment, according to new futility rules developed using phase II and III trial data.
The rules are important for preventing needless drug exposure and to minimize the development of drug-resistant variants in patients with little or no chance of achieving sustained virologic response, reported Dr. Nathalie Adda of Vertex Pharmaceuticals Inc., Cambridge, Mass., and her colleagues.Continue reading @ GI and HEPATOLOGY News
Pegylated interferon and ribavirin
Reported by Reuters; About one in six of the estimated 5 million U.S. patients with chronic hepatitis C (HCV) has a contraindication to standard treatment with pegylated interferon and ribavirin, researchers say.
The study published online January 7 in Alimentary Pharmacology & Therapeutics included 45,690 hepatitis C patients diagnosed between 2004 and 2009, a reported 7,903 or 17.3% were found to have contraindications to therapy. Notably the majority - 6,928, (87.6%) had only one contraindication.
The most common contraindications were bipolar disorders (6.5%), anemia (5.9%), and pregnancy (1.9%). The study concluded, "Clinical assessment of contraindications as relative and/or modifiable should be considered and used to determine if patients could benefit from current pegylated-interferon–containing triple therapy or future pegylated-interferon– or ribavirin-free regimens.
"Dr. Andrew H. Talal from the State University of New York, Buffalo, told Reuters Health by email. "The fact that the majority of the contraindications are reversible or readily treatable was another surprising aspect."
This study was funded in part by Genentech Inc. and F. Hoffmann-La Roche Ltd; some of the authors are employees of Genentech.
Read the article here, or the full text published in Alimentary Pharmacology & Therapeutics.
In Todays News - Treatment response improved neurocognitive function in patients with chronic HCV
Patients with chronic HCV who responded to treatment with pegylated interferon and ribavirin experienced a subsequent improvement to neurocognitive performance in a recent study.
Continue reading....
Hepatitis C In Elderly Patients
Commentary: efficacy and safety of ribavirin plus pegylated interferon-alpha in geriatric patients with chronic hepatitis C
The study of Hu et al. from Taiwan adds evidence on the safety and efficacy of treatment with pegylated interferon-alpha plus ribavirin (PR) in elderly patients with chronic hepatitis C virus (HCV) infection.......
Possibly the development of new all oral HCV therapies with direct-acting antivirals will become the standard of care in the difficult to treat HCV patients, including the elderly.
Read more here.....
Research - Hepatitis C Genotypes
New Ways to Study HCV, Genotypes 3 and 4
Posted on January 21, 2013
by Kristine Novak, PhD, Science Editor
Researchers can now study replication of Hepatitis C virus genotypes 3 and 4 in cultured cells, described in 2 articles in the January issue of Gastroenterology. These new tools will improve our understanding of how they cause liver disease, and could lead to new treatments.
There are 6 major HCV genotypes. Genotypes 1 and 2 are the most prevalent in North America, Europe, and Japan, and are the most highly studied. However, other genotypes have specific characteristics. Genotype 3a infection can cause hepatic steatosis, and is more resistant to treatment with telaprevir and boceprevir. Genotype 4 is prevalent in the Middle East and many African countries, and is becoming more common in central and northern Europe; it accounts for 93% of HCV infections in Egypt, and 5%–15% of infections in several European countries....
Continue reading....
Today From Medscape
IL28B Polymorphisms Predict Response to Therapy Among Chronic Hepatitis C Patients With HCV Genotype 4
Discussion Only
View full text @ Medscape
This study confirms that SNP near IL28B strongly predicts virological response to therapy among chronic hepatitis C with HCV-4. Although HCV-4 was initially branded as a 'difficult-to-treat' genotype, recent data, especially from Egypt, where HCV-4 represents >90% of HCV infections,[14] have suggested SVR rates between 43 and 70%, that is, intermediate between those reported for HCV-1 and HCV-2 or HCV-3.[14]
Major factors influencing response are Egyptian origin, absence of advanced fibrosis and insulin resistance – measured as homoeostasis model assessment of insulin resistance or homoeostasis model assessment of insulin resistance (HOMA-IR).[15]
As multivariate analyses have shown that polymorphisms near IL28B are the strongest predictors of response to therapy among HCV-1, and much less so in HCV-2 and -3,[3–7] the interest of studying these genetic variants as predictors of response in HCV-4 is obvious. The amount of available data is, however, limited and often gathered on ethnically heterogeneous populations of patients. Three series reported patients monoinfected with HCV: one analysed 102 cases from Austria (97% from Egypt),[8] another on 103 patients from Milan, Italy (68% from Egypt)[9] and a third on 82 patients from different ethnic groups (51% Egyptians, 34% Europeans and 13.4% Sub-Saharan Africans).[10] These studies identified several baseline predictors of SVR in HCV-4: female sex,[9]rs12979860 CC genotype,[8–10] Egyptian ethnicity,[9] low stages of liver fibrosis[8,9] or low viral load.[8,10]
In two additional studies on small series of patients (n = 13 and n = 23, respectively) coinfected with HCV and HIV[11,12] suggest that both viremia and low stages of fibrosis predicted response independently of IL28B SNP, although in the larger study patients with HCV-1 and HCV-4 were pooled together, rendering the analysis difficult. Our present study, the largest to date on patients of homogeneous ancestry (all from Middle East), confirms the strong predictive value of IL28B genotypes on SVR, and, indeed, predictors of SVR were similar to those previously reported, with the exception of SNP at marker rs12979860 being replaced by rs8099917. In our series, in fact, both the absence of advanced fibrosis and polymorphisms near IL28B were independent predictors of SVR, confirming that algorithms of treatment for HCV-4 should include at least these two variables.
Additional prospective analyses are warranted to ascertain whether on-treatment variables should also be considered, for example, to tailor therapy duration in patients with rapid virological response (RVR). In general, in HCV-monoinfected patients with HCV-4, IL28B polymorphisms do not seem to predict SVR in patients who have achieved RVR.[8,9] However, IL28B genotype may be included in treatment algorithms to tailor therapy among patients who have failed to achieve RVR.[9] In the study from Milan,[9] HCV-4 non-RVR patients with CT/TT genotypes at marker rs12979860 had SVR rates as low as 23%, compared with 75% reached by patients with the CC genotype. These Authors stated that lack of RVR in patients with unfavourable IL28B genotypes should not be considered as a univocal stopping rule; however, premature therapy termination should be considered in cases with severe treatment side effects, poor motivation or severe comorbidities.[9] In our study, we could not collect data on RVR.
Thus, also given the small sample size of studies conducted so far, additional prospective studies are warranted to assess the predictive value of IL28B polymorphisms on the virological response to therapy among HCV-4, possibly assessing the impact of liver fibrosis stage, HOMA-IR score and on-treatment viral response relative to IL28B genotypes.
Thus, IL28B polymorphisms are strong predictors of virological response also in chronic hepatitis C with HCV-4, confirming previous reports[8–12] and extending data on spontaneous eradication.[15] Interestingly, IL28B SNP do not seem to predict viral response to therapy among patients with HCV-5 from the same genetic ancestry as the present study.[16] Whether these polymorphisms may be used to tailor therapy duration in patients with HCV-4 remains to be determined by larger prospective studies.
Free registration required, full text available here
Do HCV Patients Still Need A Liver Biospy In 2013?
Today From Medscape
IL28B Polymorphisms Predict Response to Therapy Among Chronic Hepatitis C Patients With HCV Genotype 4
Discussion Only
View full text @ Medscape
This study confirms that SNP near IL28B strongly predicts virological response to therapy among chronic hepatitis C with HCV-4. Although HCV-4 was initially branded as a 'difficult-to-treat' genotype, recent data, especially from Egypt, where HCV-4 represents >90% of HCV infections,[14] have suggested SVR rates between 43 and 70%, that is, intermediate between those reported for HCV-1 and HCV-2 or HCV-3.[14]
Major factors influencing response are Egyptian origin, absence of advanced fibrosis and insulin resistance – measured as homoeostasis model assessment of insulin resistance or homoeostasis model assessment of insulin resistance (HOMA-IR).[15]
As multivariate analyses have shown that polymorphisms near IL28B are the strongest predictors of response to therapy among HCV-1, and much less so in HCV-2 and -3,[3–7] the interest of studying these genetic variants as predictors of response in HCV-4 is obvious. The amount of available data is, however, limited and often gathered on ethnically heterogeneous populations of patients. Three series reported patients monoinfected with HCV: one analysed 102 cases from Austria (97% from Egypt),[8] another on 103 patients from Milan, Italy (68% from Egypt)[9] and a third on 82 patients from different ethnic groups (51% Egyptians, 34% Europeans and 13.4% Sub-Saharan Africans).[10] These studies identified several baseline predictors of SVR in HCV-4: female sex,[9]rs12979860 CC genotype,[8–10] Egyptian ethnicity,[9] low stages of liver fibrosis[8,9] or low viral load.[8,10]
In two additional studies on small series of patients (n = 13 and n = 23, respectively) coinfected with HCV and HIV[11,12] suggest that both viremia and low stages of fibrosis predicted response independently of IL28B SNP, although in the larger study patients with HCV-1 and HCV-4 were pooled together, rendering the analysis difficult. Our present study, the largest to date on patients of homogeneous ancestry (all from Middle East), confirms the strong predictive value of IL28B genotypes on SVR, and, indeed, predictors of SVR were similar to those previously reported, with the exception of SNP at marker rs12979860 being replaced by rs8099917. In our series, in fact, both the absence of advanced fibrosis and polymorphisms near IL28B were independent predictors of SVR, confirming that algorithms of treatment for HCV-4 should include at least these two variables.
Additional prospective analyses are warranted to ascertain whether on-treatment variables should also be considered, for example, to tailor therapy duration in patients with rapid virological response (RVR). In general, in HCV-monoinfected patients with HCV-4, IL28B polymorphisms do not seem to predict SVR in patients who have achieved RVR.[8,9] However, IL28B genotype may be included in treatment algorithms to tailor therapy among patients who have failed to achieve RVR.[9] In the study from Milan,[9] HCV-4 non-RVR patients with CT/TT genotypes at marker rs12979860 had SVR rates as low as 23%, compared with 75% reached by patients with the CC genotype. These Authors stated that lack of RVR in patients with unfavourable IL28B genotypes should not be considered as a univocal stopping rule; however, premature therapy termination should be considered in cases with severe treatment side effects, poor motivation or severe comorbidities.[9] In our study, we could not collect data on RVR.
Thus, also given the small sample size of studies conducted so far, additional prospective studies are warranted to assess the predictive value of IL28B polymorphisms on the virological response to therapy among HCV-4, possibly assessing the impact of liver fibrosis stage, HOMA-IR score and on-treatment viral response relative to IL28B genotypes.
Thus, IL28B polymorphisms are strong predictors of virological response also in chronic hepatitis C with HCV-4, confirming previous reports[8–12] and extending data on spontaneous eradication.[15] Interestingly, IL28B SNP do not seem to predict viral response to therapy among patients with HCV-5 from the same genetic ancestry as the present study.[16] Whether these polymorphisms may be used to tailor therapy duration in patients with HCV-4 remains to be determined by larger prospective studies.
Free registration required, full text available here
Do HCV Patients Still Need A Liver Biospy In 2013?
Over at CCO the age old debate lives on rather hepatitis C patients still need a liver biopsy for assessing liver damage, in the article one physician is satisfied with today's non-invasive methods, Mark S. Sulkowski MD writes; "With interferon-free, all-oral therapies on the near-term horizon, I am increasingly comfortable relying on patient history, physical exam, routine laboratory tests, and liver imaging as well as noninvasive serum markers to obtain a picture of liver health.."
View all links to the article here, along with a review of imaging technology developed by Mayo to detect liver fibrosis called Magnetic Resonance Elastography, or MRE.
2013-Guide to Clinical Trials for People with Hepatitis C
This month TAG published an insightful second edition guide to hepatitis C clinical trials, written by Tracy Swan and Matt Sharp.
Of Interest
A Study of TMC435 in Combination With PSI-7977 (GS7977) in Chronic Hepatitis C Genotype 1-Infected Prior Null Responders To Peginterferon/Ribavirin Therapy or HCV Treatment-Naive Patients
Hepatitis C - 8 Clinical Trials For: Sofosbuvir (GS-7977)
Hepatocellular carcinoma (HCC)
This week in an analysis of HALT-C data, investigating the surveillance of liver cancer in academic centers published by the American Journal of Gastroenterology, reported only 20% of hepatocellular carcinoma (HCC), was found at a very early stage.
The primary goal of the HALT-C Trial was to determine if ongoing therapy with pegylated interferon monotherapy could suppress the Hepatitis C virus and slow disease progression, including the development of liver cancer in patients who were not able to achieve SVR using pegylated interferon and ribavirin.
Full text is available here
Liver Cirrhosis
When the Spleen Gets Tough, the Varices Get Going
Published in Gastroenterology - Volume 144, Issue 1, January 2013
In this era of personalized medicine, it is necessary to stratify different risk groups among patients with cirrhosis. As recently proposed, a revised staging of cirrhosis should start with its main classification of compensated and decompensated cirrhosis, 2 separate entities with different prognostic significance. Decompensated cirrhosis is defined by the presence of complications that are mostly secondary to portal hypertension: Ascites, variceal hemorrhage, and/or hepatic encephalopathy. Compensated cirrhosis would in turn be composed of 2 substages: Without varices or with varices. These 2 substages of compensated cirrhosis also have different prognostic significance; patients without varices have a significantly better survival than those with varices....Full text available here...
Liver Cirrhosis - Poor Sleep, Depression and Anxiety
Published January 22 2013 online at BMC Gastroenterology;
Studies have shown psychological distress in patients with cirrhosis, yet no studies have evaluated the laboratory and physiologic correlates of psychological symptoms in cirrhosis. This study therefore measured both biochemistry data and heart rate variability HRV analysis, and aimed to identify the physiologic correlates of depression, anxiety, and poor sleep in cirrhosis. The found; increased serum AST and abnormal autonomic nervous activities by HRV analysis were associated with psychological distress in cirrhosis. Because AST is an important mediator of inflammatory process, further research is needed to delineate the role of inflammation in the cirrhosis comorbid with depression.
Download PDF here
Of Interest - Hepatitis C and Sleep
BMS-986094 Lawsuit
We heard more on the lawsuit involving 15 patients who were tragically hurt - one died- during the company-sponsored clinical trials of the hepatitis C drug BMS-986094. On Thursday The Wall Street Journal reported that Bristol-Myers Squibb agreed to pay $80 million to 15 patients who were harmed during the clinical trials.
Read the story @ WSJ
HCV Transmission - The Tattoo
Reuters Reports - Hepatitis C linked to ink
(Reuters Health) - Researchers are hoping that people will do some research about where to get a tattoo, after a study found a link between body art and hepatitis C.The new study found that people with the virus were almost four times more likely to report having a tattoo, even when other major risk factors were taken into account, co-author Dr. Fritz Francois of New York University Langone Medical Center told Reuters Health.
Although the study could not prove a direct cause and effect, "Tattooing in and of itself may pose a risk for this disease that can lay dormant for many, many years," Francois said.The abstract is available here, the article here.
Related @ Healio.com/Hepatology
If tattoos came with ‘fine print’ warnings…
Hepatitis C risk increases for anyone who gets one or more tattoos.
Read more.
HCV Transmission In A Clinical Setting
A Second New York hospital warns of potential HIV, hepatitis C or hepatitis B infection
A second western New York hospital is notifying patients that they may have been exposed to HIV, hepatitis B or hepatitis C through the improper sharing of insulin pens, hospital officials said Thursday.
Olean General Hospital was mailing letters to 1,915 patients who received insulin at the hospital from November 2009 through last week, advising them to call to arrange for blood testing. The risk of infection is very low, hospital officials said, but they wanted patients to be aware of the possibility.
Hospital officials said the action follows an internal review conducted after the Veterans Affairs hospital in Buffalo discovered more than 700 patients may have been exposed to blood-borne pathogens over a two-year period when multi-use pens intended for use by a single patient may have been used on more than one person.
“Interviews with nursing staff indicated that the practice of using one patient’s insulin pen for other patients may have occurred on some patients,” said Timothy Finan, president and chief executive of Upper Allegheny Health System, the parent company of the Olean hospitalContinue reading......
Liver Health - Don’t Double Up on Acetaminophen
You have flu symptoms, so you've been getting some relief for the past two days by taking a cough and flu medicine every few hours. Late in the day, you have a headache and you think about grabbing a couple of acetaminophen tablets to treat the pain.
Stop right there.
What you may not realize is that more than 600 medications, both prescription and over-the-counter (OTC), contain the active ingredient acetaminophen to help relieve pain and reduce fever. Taken carefully and correctly, these medicines can be safe and effective. But taking too much acetaminophen can lead to severe liver damage.
Acetaminophen is a common medication for relieving mild to moderate pain from headaches, muscle aches, menstrual periods, colds and sore throats, toothaches, backaches and to reduce fever. It is also used in combination medicines, which have more than one active ingredient to treat more than one symptom.
'Tis Cold and Flu Season
The National Institutes of Health (NIH) says that Americans catch one billion colds per year and as many as 20% of Americans get the flu. Moreover, 7 in 10 Americans use OTC medicines to treat cold, cough and flu symptoms.
Fathia Gibril, M.D., M.HSc., a supervisory medical officer at the Food and Drug Administration (FDA), explains that consumers looking for relief from a cold or the flu may not know that acetaminophen comes in combination with many other medications used to treat those symptoms. "So if you're taking more than one medicine at a time," she says, "you may be putting yourself at risk for liver damage."
Symptoms of acetaminophen overdose may take many days to appear, and even when they become apparent, they may mimic flu or cold symptoms. The current maximum recommended adult dose of acetaminophen is 4,000 milligrams per day, To avoid exceeding that dose:
- don't take more than one OTC product containing acetaminophen,
- don't take a prescription and an OTC product containing acetaminophen, and
- don't exceed the recommended dose on any product containing acetaminophen.
FDA has an online list of brand names of products
containing acetaminophen8.
Rely on Health Care Experts
Acetaminophen is used in many commonly prescribed medications in combination with pain relievers such as codeine, oxycodone and hydrocodone. As of January 2011, FDA reported that overdoses from prescription medicines containing acetaminophen accounted for nearly half of all cases of acetaminophen-related liver injury in the U.S. When your health care professionals prescribe a drug, be sure to ask if it contains this active ingredient, and also to inform them of all other medicines (prescription and OTC) and supplements you take.
Even if you still have fever or pain, it's important not to take more than directed on the prescription or package label, notes FDA supervisory medical officer Sharon Hertz, M.D. But be careful, the word "acetaminophen" is not always spelled out in full on the container's prescription label. Abbreviations such as APAP, Acetaminoph, Acetaminop, Acetamin, or Acetam may be used instead.
When buying OTC products, Hertz suggests you make it a habit of telling the pharmacist what other medications and supplements you’re taking and asking if taking acetaminophen in addition is safe.
When the medicine is intended for children, the "Directions" section of the Drug Facts label tells you if the medicine is right for your child and how much to give. If a dose for your child's weight or age is not listed on the label and you can't tell how much to give, ask your pharmacist or doctor what to do.
If you're planning to use a medication containing acetaminophen, you should tell your health care professional if you have or have ever have had liver disease.
Acetaminophen and alcohol may not be a good mix, either, Hertz says. If you drink three or more alcoholic drinks a day, be sure to talk to your health care professional before you use a medicine containing acetaminophen.
This article appears on FDA's Consumer
Updates page9, which features
the latest on all FDA-regulated products.
January 24, 2013Related - Hepatitis C and Tylenol
Written by
The most common question I am asked by hepatitis C patients, “Is Tylenol (acetaminophen or paracetamol as it is called in other countries) safe for the liver? The answer is, “Yes, if taken as directed.”Read the full article @ http://lucindaporterrn.com/blog/
Liver Health - Binge Drinking
Binge drinking will exacerbate liver injury, especially if comorbid conditions such as obesity, Hepatitis C, or HIV infection exist.
Alcoholic liver disease (ALD) is characterized by a fatty liver, hepatitis, fibrosis, and cirrhosis. Binge drinking is on the rise worldwide, and is particularly common in the U.S. A review of studies addressing the effects of binge drinking on the liver underscores the complex interactions among various immune, signaling pathways, epigenetic, and metabolic responses of the liver to binge drinking.
"Therefore, people should not binge drink, especially on an empty stomach, and if they are chronic heavy drinkers, binge drinking will exacerbate liver injury, especially if comorbid conditions such as obesity, Hepatitis C, or HIV infection exist."Continue reading....
Heavy Alcohol Use Increases Liver Cancer Risk for People with Hepatitis B
Hepatitis B patients with liver cirrhosis who consumed large amounts of alcohol were more likely to develop hepatocellular carcinoma than people who drank less, according to a report in the December 6, 2012, online edition of the Journal of Hepatology .Read more @ HIV and Hepatitis
In Todays News - Liver Health
DGNews
FDA: Significant Liver Injury Associated With Use of Tolvaptan
ROCKVILLE, Md -- January 25, 2013 -- The US Food and Drug Administration (FDA) and Otsuka pharmaceuticals are notifying healthcare professionals of significant liver injury associated with the use of tolvaptan (Samsca).
In a double-blind, 3-year, placebo-controlled trial in about 1,400 patients with autosomal dominant polycystic kidney disease (ADPKD) and its open-label extension trial, 3 patients treated with the drug developed significant increases in serum alanine aminotransferase (ALT) with concomitant, clinically significant increases in serum total bilirubin.
In the trials the maximum daily dose of tolvaptan administered (90 mg in the morning and 30 mg in the afternoon) was higher than the maximum 60 mg daily dose approved for the treatment of hyponatremia.
Most of the liver enzyme abnormalities were observed during the first 18 months of therapy. Following discontinuation of treatment, all 3 patients improved.
An external panel of liver experts assessed these 3 cases as being either probably or highly likely to be caused by tolvaptan.
These findings indicate that tolvaptan has the potential to cause irreversible and potentially fatal liver injury.
These data are not adequate to exclude the possibility that patients receiving tolvaptan for its indicated use of clinically significant hypervolemic and euvolemic hyponatremia are at a potential increased risk for irreversible and potentially fatal liver injury.
Tolvaptan is a selective vasopressin V2-receptor antagonist indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia. Tolvaptan is not approved for the treatment of ADPKD.
Recommendations for Healthcare Professionals:
· Healthcare providers should perform liver tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice.
· If hepatic injury is suspected, tolvaptan should be promptly discontinued, appropriate treatment should be instituted, and investigations should be performed to determine probable cause.
· Tolvaptan should not be re-initiated in patients unless the cause for the observed liver injury is definitively established to be unrelated to treatment with Samsca.
Healthcare professionals and patients are encouraged to report adverse events or side effects related to the use of this product to the FDA's MedWatch Safety Information and Adverse Event Reporting
Program:
· Complete and submit the report Online: https://www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm
http://www.fda.gov/Safety/HowToReport/DownloadForms/default.htm
Forms or call 1-800-332-1088 to request a reporting form, then complete and return to the address on the pre-addressed form, or submit by fax to 1-800-FDA-0178
SOURCE: US Food and Drug Administration
Published Today - In The Current Issue Of GI & Hepatology News
AASLD - Ribavirin induced anemia
BY N E I L OSTERWEIL
IMNG Medical News BOSTON
Cirrhotic patients have similar hepatitis C virus SVRs when treated with either ribavirin dose reduction or erythropoietin
Anemia developed significantly more often among patients with hepatitis C virus infection and compensated cirrhosis than among noncirrhotic patients during triple therapy in a randomized, open-label trial of treatment-naive patients, but in most instances the anemia was effectively treated.
In an anemia management subanalysis of a study comparing sustained virologic response (SVR) rates in cirrhotic and noncirrhotic patients treated with boceprevir (Victrelis), pegylated interferon alfa-2b (Peg-Intron), and ribavirin (RBV), 57% of patients with cirrhosis and anemia treated with a ribavirin dose reduction had an SVR, compared with 64% of those treated with erythropoietin.
Among noncirrhotic patients with anemia, the respective SVR rates were 73% and 72%. None of the differences between those treated with a RBV dose reduction or erythropoietin was significant in cirrhotic and noncirrhotic patients, Dr. Eric J. Lawitz, AGAF, reported at the annual meeting of the American Association for the Study of Liver Diseases. ª
Sustained viral responses are comparable in cirrhotic patients when anemia is managed by ribavirin dose reduction or erythropoietin,º said Dr. Lawitz, medical director and principal investigator at Alamo Medical Research in San Antonio.
He also noted that ribavirin dose reductions should be the initial strategy for managing anemia, followed, if necessary, by erythropoietin. In the trial, 687 treatment-naive patients with hepatitis C virus (HCV) infections were treated for 4 weeks with pegylated interferon (PEG-IFN) alfa-2b and RBV, then 24 or 44 weeks of boceprevir added in.
Baseline hemoglobin (Hb) levels ranged from 12 g/dL to 15 g/dL for women, and from 13 g/dL to 15 g/dL for men. Patients with Hb approaching 10 g/dL or less (tested from baseline through week 48) were randomized to either ribavirin dose reduction (249 patients) in 200-mg increments (first increment of 400 mg for initial 1,400-mg daily doses) at the investigators' discretion, or to erythropoietin (251 patients) at 40,000 U/week, modifiable to 20,000 U/week or 60,000 U/week at the investigator's discretion.
The remaining patients received anemia prophylaxis but were not randomized. If the Hb level dropped to 8.5 g/dL, patients could receive the other treatment as a secondary intervention, and patients with Hb 7.5 g/dL were discontinued from all study drugs.
Primary efficacy measures for all patients (cirrhotic and noncirrhotic) in each anemia strategy group were identical, with 82% having an end-oftreatment response, 71% having an SVR, and 10% experiencing relapse. Among cirrhotic vs. noncirrhotic patients, rates were 68% vs. 76% for end-of-treatment response , 55% vs. 64% for SVR, and 18% vs. 11% for relapse. Patients with cirrhosis were significantly more likely to require a secondary anemia intervention (44% vs. 26%, P = .009).
Among noncirrhotic patients (but not cirrhotic patients), a secondary anemia intervention was associated with a greater likelihood of SVR (80% vs. 70% for only one intervention, P = .05).
Serious adverse events occurred in 20% of cirrhotic patients and 12% of noncirrhotic patients, but only one study death occurred. The noncirrhotic patient died of a cardiac arrest, which was considered to be unrelated to therapy.
Treatment-emergent adverse events occurred in 3% of patients with cirrhosis and 2% of those without cirrhosis. Drug discontinuation for adverse events occurred in 17% of cirrhotic patients, and 16% of noncirrhotic patients, according to Dr. Lawitz.
Cirrhotic patients were more likely to have Hb concentrations ranging from 6.5 to 8.0 g/dL than were noncirrhotic patients, but no patient in either group had an Hb concentration below 6.5 g/dL.
Neutrophil counts in the range of 500-749/mm3 occurred in 24% of cirrhotic patients and 27% of noncirrhotic patients, and counts below 500/mm3 were seen in 20% and 12%. Platelet counts from 25,000 to 49,999/mm3 occurred in 22% of cirrhotic patients and 2% of noncirrhotic patients.
Counts below 25,000/mm3 were seen in 3% vs. less than 1%, respectively. Transfusion rates were similar between the groups.
AASLD - New interferon speeds HCV virologic responses
BY N E I L OSTERWEIL IMNG
Medical News BOSTON
Call it interferon 3.0. An investigational form of the immunomodulator, known as interferon- lambda, appeared to be effective against chronic hepatitis C virus infections, but had fewer side effects than interferon alfa, in two separate clinical trials.
In a phase IIb study, ribavirin plus pegylated interferon-lambda-1a (IFNL/ RBV) was comparable in efficacy to ribavirin plus pegylated interferon alfa-2a (PEG-IFN/RBV) in treatment- naive patients with hepatitis C (HCV) genotype 1 or 4 viral infections, Dr. Andrew J. Muir reported at the annual meeting of the American Association for the Study of Liver Diseases.
The improved tolerability, together with a faster time to virologic response, supports the further assessment of lambda-based, directacting antiviral combination regimens in patients chronically infected with HCV genotypes 1 or 4,º said Dr. Muir, clinical director of hepatology in the department of medicine at Duke University Medical Center, Durham, N.C.
In a separate small study also presented at the meeting, IFN-L/RBV, combined with a direct-acting antiviral agent, yielded high rates of sustained virologic response (SVR) in Japanese patients with HCV genotype 1b infections, said Dr. Namiki Izumi of Musashino Red Cross Hospital in Tokyo. IFN-L is a type III interferon with strong antiviral activity but a restricted receptor distribution that is reputed to give the drug a better tolerability profile than the alfa interferons currently in widespread clinical use.
Comparing New and Old IFNs
In the EMERGE phase IIb study, Dr. Muir and his colleagues randomized 527 noncirrhotic, treatment-naive adults with HCV genotypes 1-4 on a 1:1:1:1 basis to either PEG-IFN 180 mcg weekly plus daily ribavirin or IFN-L at dose levels of 120, 180, or 240 mcg weekly plus daily ribavirin.
Because of safety issues, patients with genotypes 1 and 4 assigned to receive the 240-mcg dose of IFN-L had their dose reduced to 180 mcg at study week 12, and this dose level was subsequently chosen for phase III trials.
Dr. Muir reported results through 72 weeks of follow-up for 407 patients with genotypes 1 or 4 treated for 48 weeks. Approximately 60% of patients in each of the four treatment arms completed treatment and follow-up. IFN-L at the 180-mcg dose was associated with significantly more rapid virologic responses at week 4 (RVR4 14.7% vs. 5.8%) and complete early virologic responses at week 12 (55.9% vs. 36.9%) than was PEG-IFN (P less than .05 for each comparison).
However, there were no significant differences in response rates at either the end of treatment or in SVR24 at last follow-up, and relapse rates were similar between the groups.
Adverse events of any grade were similar among the groups, except for lower percentages of myalgia (5.9% for IFN-L vs. 33.0% for PEG-IFN), pyrexia (7.8% vs. 33%, respectively), chills (3.9% vs. 21.4%), and arthralgia (5.9% vs. 20.4%). Treatment-emergent liver abnormalities included alanine aminotransferase (ALT) 5 to 10 times the upper limit of normal in 2.9% of patients on IFN-L, compared with 4.9% for those on PEG-IFN.
In contrast, total bilirubin levels 2.6 to 5 times the upper limit of normal were seen in 5% vs. 3.9%, respectively. In both the 120-mcg and 180- mcg IFN-L groups and the PEG-IFN group, 1% of patients required dose reductions due to liver-related lab abnormalities. In all, 2.9% of patients of IFN-L discontinued the drug for liver abnormalities, compared with 1.9% for PEG-IFN.
High SVR With Lambda and Direct- Acting Antivirals
In the D-LITE study, Dr. Izumi and her colleagues compared IFN-L/RBV in combination with either daclatasvir, an investigational viral NS5A replication complex inhibitor, or asunaprevir, an investigational NS3 protease inhibitor, with each group including a placebo for the alternate direct-acting antiviral agent. (For example, patients receiving IFN-L/RBV and daclatasvir also received an asunaprevir placebo.)
In addition, the trial contained a substudy arm with patients assigned to PEG-IFN/RBV with daclatasvir and asunaprevir placebos; Dr. Izumi reported only on the IFN-L arms. All patients in the IFN-L groups were treated for 24 weeks, at which point those patients who did not have a protocol-defined response (PDR) were given an additional 24 weeks of treatment.
A PDR was defined as an HCV RNA level at week 4 below the lower limit of quantification (less than 25 IU/mL) and undetectable HCV RNA at 12 weeks.
In the daclatasvir group, eight of eight patients had a PDR, compared with five of six in the asunaprevir arm. The single patient without a response in the latter arm discontinued therapy for an adverse event during week 3.
All eight patients in the daclatasvir arm and the five remaining patients in the asunaprevir arm had week 4 and week 12 sustained virologic responses (SVR4 and SVR12).
Grade 3 or 4 adverse events occurred in one of eight patients on daclatasvir, and in four of five on asunaprevir.
There were no grade 3 or 4 lab abnormalities among patients on daclatasvir. In the asunaprevir group, there was one case of hemoglobin abnormalities, three with elevated ALT, four with elevated aspartate aminotransferase, and one with elevated total bilirubin.
The authors concluded that the combination of IFN-L/RBV and daclatasvir had the best safety profile, and that the data support further investigation of the combination in patients with HCV genotype 1b.
Both the EMERGE IIb and DLITE studies were supported by Bristol-Myers Squibb.
Dr. Muir reported receiving grant and research support and serving on advisory committees or review panels for the company.
Dr. Izumi reported receiving speaking and teaching fees from the company.
AASLD - Triple therapy has poor safety in cirrhotic hepatitis C
BY N E I L OSTERWEIL IMNG
Medical News BOSTON
In patients with chronic hepatitis C virus infections and compensated cirrhosis, a combination of a direct-acting antiviral agent, pegylated interferon, and ribavirin produced high on-treatment virologic response rates, but at the cost of significantly increased toxicities in an interim analysis of a French multicenter trial.
Although the efficacy of direct-acting antiviral regimens involving the protease inhibitors telaprevir (Incivek) and boceprevir (Victrelis) combined with pegylated interferonalfa-2a or -2b in combination with ribavirin (PEG-IFN/RBV) in cirrhotic nonresponders to prior therapy was good, their safety was ª poor,º said Dr. Christophe Hézode of Hôpital Henri Mondor, Créteil, France.
Virologic response at 16 weeks in a per-protocol analysis was 92% with telaprevir and 77% with boceprevir. However, there were increased rates of serious adverse events and more difficult-to-manage anemia than in phase III trials for telaprevir and boceprevir, which included only a few patients with cirrhosis, Dr. Hézode said at the annual meeting of the American Association for the Study of Liver Diseases.
In treatment-experienced cirrhotic patients with platelet counts of 100,000/mm3 or serum albumin levels below 35 g/L, clinicians should treat on a case-by-case basis because of the high risk for severe complications, Dr. Hézode said. Cirrhotic experienced patients without predictors of severe complications should be treated, but carefully monitored, he added.
Dr. Hézode and his coauthors in the French Cohort of Therapeutic Failure and Resistances in Patients Treated With a Protease Inhibitor(telaprevir or boceprevir), Pegylated Interferon, and Ribavirin (CUPIC) trial studied two cohorts of patients with chronic hepatitis C virus (HCV) infections, and compensated cirrhosis (Child Pugh class A) who had relapsed or had only a partial response to prior therapy, with partial response defined as at least a 2 log10 decline in HCV RNA but failure to clear virus by week 24.
He presented data on 497 patients who had completed 16 weeks of therapy on one of two regimens. In one cohort, 292 patients received 12 weeks of telaprevir 750 mg every 8 hours, and PEG-IFN alfa-2a (Pegasys) 180 mcg/wk with ribavirin 1,000-1,200 mg/day, followed by PEG-IFN/RBV through 48 weeks. In the second cohort, patients received a 4-week initiation phase with PEG-IFN alfa-2b (PegIntron) and ribavirin, followed by 44 weeks of boceprevir 800 mg every 8 hours, PEG-IFN 1.5 mcg/kg per wk, and ribavirin 800-1,400 mg/day.
At week 16, 45% of patients on telaprevir had had at least one serious adverse event, with 14.7% ending therapy because of a serious side effect. In all, 22.6% discontinued therapy, and there were five deaths: from septicemia, septic shock, pneumopathy, endocarditis, and bleeding esophageal varices.
Other complications in this group included grade 3or 4 infections in 6.5%, grade 3 or 4 hepatic decompensation in 2%, grade 3/4 asthenia in 5.5%, and renal failure in 1.7%.
Hematologic adverse events included anemia of grade 2 or greater in 30.4%, erythropoietin use in 53.8%, blood transfusion in 16.1%, and ribavirin dose reduction in 13%.
In addition, 2.7% of patients had grade 3 or 4 neutropenia, and 1.7% had grade 3 or 4 thrombocytopenia. In the boceprevir group, 32.7% had at least one serious adverse event, 26.3% discontinued prematurely, and 7.3% discontinued because of serious events.
The cause of one death was pneumopathy. Grade 3 or 4 adverse events involved infections in 2.4%, hepatic decompensation in 2.9%, and asthenia in 5.8%.
Hematologic events included grade 2 or greater anemia in 27.8%, erythropoietin use in 46.3%, blood transfusion in 6.3%, and ribavirin dose reduction in 10.7%.
Grade 3 or 4 neutropenia was seen in 4.4%, and grade 3 or 4 thrombocytopenia in 5.4%.
Two patients (1%) in this cohort received thrombopoietin.
In a multivariate analysis, significant baseline predictors of severe complications (death, severe infection, hepatic decompensation) included platelet counts of 100,000/mm3 or lower (odds ratio, 3.11; P = .0098) and a serum albumin level below 35 g/L (OR, 6.33; P less than .0001).
Source
The Current Issue Of GI & Hepatology News
(VOL. 7 NO. 1 JANUARY 2013): Download PDF Or View Interactive Version
GI & Hepatology News is the official newspaper of the AGA Institute and provides the gastroenterologist with timely and relevant news and commentary about clinical developments and about the impact of health-care policy.
The newspaper is led by an internationally renowned board of editors.
Personal HCV Experiences
An Interview with Alan Franciscus of the Hepatitis C Support Project (Part 1)
There is a very good argument to be made that Alan Franciscus is the most significant trailblazer in his work for hepatitis C awareness and advocacy movement in the United States. Since the existence of hepatitis C as a distinct virus was not even proven until 1989, the movement has been in existence for only about twenty odd years, and it has been far from a powerful entity in terms of public awareness and reach. In fact, a good deal of what has been accomplished has been accomplished by Alan Franciscus. And the man doesn’t even have a Wikipedia page.Read the interview at Hepatitis Connect
Addicition
Christopher Kennedy Lawford who unknowingly contracted hepatitis C during his years of drug use, also wrote Healing Hepatitis C in 2009, here is his video.
In The News - Christopher Kennedy Lawford brings his story of recovery and redemption to Pasadena
By Carl Kozlowski 01/23/2013
Growing up in a world of showbiz and political privilege as the son of movie star Peter Lawford and the nephew of President John F. Kennedy, Christopher Kennedy Lawford couldn’t have imagined that alcohol and drug addiction would eventually cost him his share of the family fortune and very nearly his life.
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