William F. Balistreri, MD
Authors and Disclosures
Posted: 07/14/2010
Question
I've heard that it is now possible to predict which patients with chronic hepatitis C virus infection will respond to treatment -- is this true?
Response from William F. Balistreri, MD
Dorothy M.M. Kersten Professor of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Medical Director, Liver Transplantation Program, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
Yes -- to an extent. As we learn more about the genetic and molecular mechanisms of liver injury and repair, we will be better able to predict response to treatment and therefore tailor the therapeutic strategy. This will be especially relevant to chronic hepatitis C virus (HCV) infection; it will permit us to direct treatment resources to the patients who are most likely to benefit.
Identification of the determinants of clearance and response to treatment in HCV Infection has been a high research priority. Recovery from HCV infection and the response to standard antiviral treatment depends on host factors, viral factors, and treatment (adherence) factors. The viremia in about 30% of people who acquire HCV infection will spontaneously resolve without long-term consequences.
Differences (eg, polymorphisms) in genes encoding cytokines and other immunologic mediators partially explain spontaneous recovery from HCV.[1,2] Similarly, marked differences are possible in the degree to which individuals with chronic HCV infection respond to treatment.[3]
The currently recommended treatment for chronic HCV infection is a 48-week course of pegylated-interferon alpha α alpha-2b) or PegIFN α alpha-2a combined with ribavirin. Like spontaneous clearance, treatment-related resolution of chronic hepatitis C is associated with clearance of viremia and reduction in the risk for long-term consequences of infection.[4] Differences in candidate genes are also found in patients who respond to treatment compared with so-called nonresponders.[5-7] Patients of European ancestry have a significantly higher probability of being cured than patients of African ancestry.
Rauch and colleagues performed a genome-wide association study to screen for host genetic determinants of HCV persistence and response to therapy.[8] They compared the frequency of approximately 500,000 single nucleotide polymorphisms (SNPs) in DNA from patients with spontaneous HCV resolution and patients with persistent infection. The strongest association with spontaneous recovery was detected for rs8099917, a SNP located nearest to interleukin 28B (IL28B), the gene that encodes for IFN lambda-3. Patients who are homozygous for C at rs12979860 have a >2.5-fold increased likelihood of spontaneous resolution of HCV compared with control patients who have persistent HCV infection.[9] The frequency of the minor G allele is over-represented among patients with chronic hepatitis C compared with those with spontaneous recovery; it is also overrepresented in the subset of patients with chronic infection who do not respond to PegIFN and ribavirin compared with those who achieve a sustained virologic response. Other groups have confirmed and expanded these observations.[10-12] The association of the IL28B locus with natural and treatment-associated control of HCV suggests the importance of innate immunity and IFN lambda-3 in the pathogenesis of HCV infection.
Ge and colleagues compared the frequencies of approximately 600,000 SNPs in DNA from patients with persistent HCV infection according to their response to PegIFN and ribavirin.[12] They reported that a genetic polymorphism near the IL28B gene was associated with a 2-fold change in response to treatment, among patients of European ancestry and those of African-American ancestry.[12] The C/C genotype, associated with a better response, is more frequent in European than African populations. This genetic polymorphism also explains much of the difference in response rates between black patients and patients of European ancestry. Patients who were homozygous for the T/T genotype were less likely to respond to treatment. Thus, the global distribution of the protective C/C allele correlates strongly with ethnic differences in spontaneous resolution of HCV and in treatment-related response.[12,13]
What functional mechanism underlies the IL28B response? HCV RNA triggers production of type 1 interferons by hepatocytes; these molecules stimulate transcription of interferon-stimulated genes (ISGs). Exogenous (therapeutic) interferon alpha signals similarly. Given that the polymorphism 3-kb upstream of IL28B appears to be associated with natural clearance as well as treatment response, it seems likely that the gene product is involved in the innate control of HCV. Indeed, IFN lambda has antiviral activity against genotype 1 HCV in vitro and in vivo.
Data presented at Digestive Disease Week 2010 further indicated that we can predict sustained virologic response on the basis of emerging validation of the genetic variation in regulation of the immune response to HCV.[13] The specific IL28B polymorphism (C/C, which occurs in up to 33% of patients) is strongly associated with reduced expression of intrahepatic ISGs and the response rate to PegIFN and ribavirin. Genetic variation in IL28B regulates the innate immune response to HCV in the liver, priming patients for a stronger response to exogenous IFN alpha therapy.[13]
Thus, at least 5 independent studies provide overwhelming genetic evidence for the role of IL-28B in the pathogenesis of HCV infection and in spontaneous and treatment-related recovery from HCV infection. Future studies will link these findings to improved, and perhaps personalized, HCV treatment and prevention worldwide.
Source
Showing posts with label DDW. Show all posts
Showing posts with label DDW. Show all posts
July 15, 2010
June 27, 2010
DDW: Vitamin A Boosts Response to HCV Treatment
By John Gever, Senior Editor, MedPage Today
Published: May 05, 2010
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston and Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner
NEW ORLEANS -- Early and sustained virologic responses to standard treatment for hepatitis C virus (HCV) infection were markedly improved when patients also received high doses of vitamin A, results of a small trial showed.
After 48 weeks of treatment with standard doses of pegylated interferon-alpha2b, ribavirin (Rebetol), and 30,000 IU/day of vitamin A, 61.7% of patients had achieved sustained virologic responses, compared with 42.9% of patients taking only the standard therapies without the vitamin, Shuichi Sato, MD, of Shimane University in Izumo, Japan, said here.
The addition of vitamin A also boosted early virologic response rates assessed after 12 weeks: 70% of patients taking vitamin A plus the standard drugs had no HCV genetic matter in circulation, whereas only about 40% of patients on standard therapy alone showed viral negativity at that point.
Despite the very high doses of vitamin A tested in the 42-patient trial -- the recommended daily intake of vitamin A in the U.S. ranges from 2,310 to 3,000 IU/day for adults -- Sato said it appeared to have no adverse effects in the trial.
"There is little or no risk in a high dose of vitamin A," he said at a press conference in advance of his formal presentation at Digestive Disease Week.
Sato and other researchers had reported in 2003 that retinoic acid compounds increased expression of interferon receptors on hepatoma cells in vitro. They followed that up last year with short-term clinical results suggesting that vitamin A increased the antiviral activity of interferon and ribavirin in patients with HCV infection.
At DDW, he will be presenting data on 42 patients who received a full course of PEG-interferon and ribavirin therapy in an open-label, multicenter study.
Patients with chronic hepatitis C were randomized to receive the high dose of vitamin A, or not, in addition to the standard therapy.
A little more than half the patients were men. Mean age was about 55 and 16 patients had previously received interferon treatment.
Study treatment lasted 48 weeks in most patients, although it was extended to 72 weeks in a few patients who achieved HCV negativity between weeks 12 and 36 of therapy.
About 5% of patients assigned to the vitamin A group and 10% of control patients failed to show a sustained response at week 48 but did achieve it by week 72, Sato reported.
Discontinuations were slightly more common in the vitamin A group but not significantly so: about 15% versus 10% in the control group.
Sato said a placebo-controlled trial is planned.
Press conference moderator Kelly Tappenden, PhD, of the University of Illinois in Urbana-Champaign, called the approach "promising" but said the findings need to be confirmed in a more rigorous study.
She said the very high vitamin A dose used in the trial was noteworthy and potentially a concern, as vitamin A is known to have toxic potential.
"They really need to look carefully at how to monitor the dosing schedule," Tappenden said. "It's an issue that needs to be sorted out for a practicing clinician who is not necessarily used to working with megadoses of vitamin A."
Primary source: Digestive Disease Week
Source reference:
Sato S, et al. "Retinol supplements antiviral action of pegylated interferon and ribavirin combination therapy in patients with chronic hepatitis C: Prospective pilot study" DDW 2010; Abstract T2004.
Source
Published: May 05, 2010
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston and Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner
NEW ORLEANS -- Early and sustained virologic responses to standard treatment for hepatitis C virus (HCV) infection were markedly improved when patients also received high doses of vitamin A, results of a small trial showed.
After 48 weeks of treatment with standard doses of pegylated interferon-alpha2b, ribavirin (Rebetol), and 30,000 IU/day of vitamin A, 61.7% of patients had achieved sustained virologic responses, compared with 42.9% of patients taking only the standard therapies without the vitamin, Shuichi Sato, MD, of Shimane University in Izumo, Japan, said here.
The addition of vitamin A also boosted early virologic response rates assessed after 12 weeks: 70% of patients taking vitamin A plus the standard drugs had no HCV genetic matter in circulation, whereas only about 40% of patients on standard therapy alone showed viral negativity at that point.
Despite the very high doses of vitamin A tested in the 42-patient trial -- the recommended daily intake of vitamin A in the U.S. ranges from 2,310 to 3,000 IU/day for adults -- Sato said it appeared to have no adverse effects in the trial.
"There is little or no risk in a high dose of vitamin A," he said at a press conference in advance of his formal presentation at Digestive Disease Week.
Sato and other researchers had reported in 2003 that retinoic acid compounds increased expression of interferon receptors on hepatoma cells in vitro. They followed that up last year with short-term clinical results suggesting that vitamin A increased the antiviral activity of interferon and ribavirin in patients with HCV infection.
At DDW, he will be presenting data on 42 patients who received a full course of PEG-interferon and ribavirin therapy in an open-label, multicenter study.
Patients with chronic hepatitis C were randomized to receive the high dose of vitamin A, or not, in addition to the standard therapy.
A little more than half the patients were men. Mean age was about 55 and 16 patients had previously received interferon treatment.
Study treatment lasted 48 weeks in most patients, although it was extended to 72 weeks in a few patients who achieved HCV negativity between weeks 12 and 36 of therapy.
About 5% of patients assigned to the vitamin A group and 10% of control patients failed to show a sustained response at week 48 but did achieve it by week 72, Sato reported.
Discontinuations were slightly more common in the vitamin A group but not significantly so: about 15% versus 10% in the control group.
Sato said a placebo-controlled trial is planned.
Press conference moderator Kelly Tappenden, PhD, of the University of Illinois in Urbana-Champaign, called the approach "promising" but said the findings need to be confirmed in a more rigorous study.
She said the very high vitamin A dose used in the trial was noteworthy and potentially a concern, as vitamin A is known to have toxic potential.
"They really need to look carefully at how to monitor the dosing schedule," Tappenden said. "It's an issue that needs to be sorted out for a practicing clinician who is not necessarily used to working with megadoses of vitamin A."
Primary source: Digestive Disease Week
Source reference:
Sato S, et al. "Retinol supplements antiviral action of pegylated interferon and ribavirin combination therapy in patients with chronic hepatitis C: Prospective pilot study" DDW 2010; Abstract T2004.
Source
DDW: Telaprevir Said to Benefit Hardest HCV Cases
By John Gever, Senior Editor, MedPage Today
Published: May 08, 2010
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner
NEW ORLEANS -- Adding an investigational protease inhibitor for hepatitis C virus (HCV) to standard treatment induced rapid and sustained virologic responses in many patients with poor responses to standard therapy alone, researchers said here.
In an open-label extension study, most patients with inadequate or no responses, or who showed renewed viral activity after an initial response to pegylated interferon and ribavirin, succeeded in achieving so-called sustained virologic responses to a second course of treatment that included telaprevir, reported Andrew Muir, MD, of Duke University.
Another analysis of one of these trials also showed that, among patients with inadequate initial responses to the standard regimen, even those with risk factors predicting especially poor responses did well when telaprevir was added, Muir said.
He presented the findings in two sessions here at Digestive Disease Week and at a press conference.
Telaprevir is one of two HCV protease inhibitors now in development, the other being boceprevir. These drugs are widely expected to be the first direct antiviral drugs made available for HCV, with FDA approval possible in 2011.
One of the studies Muir presented involved 117 participants in three earlier trials in the PROVE series who were in the standard-therapy arms and failed to show sustained virologic responses. They were categorized by the type of poor response: null responders (those with little or no change in viral loads), partial responders (initial decrease of at least two logs in HCV RNA but virus still detectable at week 24), and relapses and breakthroughs.
These patients underwent a second round of treatment with PEG-interferon and ribavirin at standard doses with the addition of telaprevir at 750 mg every eight hours. All three drugs were given for 12 weeks, with interferon and ribavirin continued for an additional 12 weeks.
Patients not showing complete responses at week 24 received an additional 24 weeks of interferon and ribavirin.
Muir said more than half of patients, 59%, had sustained virologic responses to the 12 weeks of telaprevir and 24 weeks of standard therapy.
Among the 35 who ended up taking interferon and ribavirin for the full 48 weeks, 52% had sustained responses.
The shorter regimen was not very effective in the subgroup with null responses to standard therapy during the PROVE studies. Only 13% of these patients developed sustained virologic responses during the first 24 weeks. But 57% of those who stayed on therapy for 48 weeks achieved sustained responses, according to Muir.
Among the other subgroups, response rates to the 24-week regimen ranged from 60% to 92%. Only seven patients in those subgroups received 48 weeks of treatment, of whom two obtained sustained responses.
The other study presented by Muir was a post hoc subgroup analysis of responses in "difficult to cure" patients in one of the earlier trials, PROVE3. These were patients who had one or more risk factors previously known to predict poor responses to interferon and ribavirin.
These included:
PROVE3 was a randomized trial that assigned patients to interferon and ribavirin at standard doses for 48 weeks with or without 12 weeks of telaprevir, or to 24 weeks of the standard therapy plus 12 weeks of telaprevir. There was also a fourth arm, combining telaprevir and interferon without ribavirin, that was excluded from the new analysis.
Muir reported that, in each major risk-factor group, patients in both telaprevir arms did far better than those receiving the standard therapy alone.
Sustained viral responses were achieved in 44% to 61% of patients receiving telaprevir, compared with 10% to 15% of those receiving only the standard regimen (P<0.0001 for all comparisons), for the following subgroups: males, those older than 50, those with body mass index values of 25 to 30, those with BMI over 30, those with initial viral loads of more than 800,000 IU/mL, and those with bridging fibrosis or cirrhosis.
Patients with the risk factor associated with the worst outcomes -- those with no response at all to initial interferon and ribavirin treatment -- also did better with telaprevir, with 38% obtaining sustained responses.
Multivariate analysis indicated that adding telaprevir increased the chances of achieving a sustained response by nearly nine-fold (odds ratio 8.7, 95% CI 4.6 to 16.7).
In his presentations here, Muir spent little time addressing adverse effects. However, earlier reports from the PROVE series indicated that anemia and skin rashes and pruritus were relatively common with telaprevir.
Philip Schoenfeld, MD, of the University of Michigan in Ann Arbor, who moderated the press conference where Muir spoke, said the results with HCV protease inhibitors have been highly encouraging.
"These agents offer the opportunity for a revolution in the treatment of hepatitis C virus patients, achieving successful eradication of the virus in substantially more patients," he said.
In particular, Schoenfeld added, boceprevir and telaprevir offer "new hope for patients who have failed conventional therapies."
Primary source: Digestive Disease Week
Source reference:
Muir A, et al "Final results of a rollover study assessing telaprevir in combination with peginterferon alfa-2a and ribavirin in chronic HCV patients with well-characterized null response, partial response, viral breakthrough, or relapse after prior PR treatment" DDW 2010; Abstract 311.
Additional source: Digestive Disease Week
Source reference:
Muir A, et al "Improved sustained virologic response (SVR) in "difficult-to-cure" patients treated with telaprevir (T) in combination with peginterferon alfa-2a (P) and ribavirin (R): An analysis from the PROVE3 study" DDW 2010; Abstract T2002
Source
Also See: DDW: New Drug Treatments Hold Promise for Hepatitis C Patients
Published: May 08, 2010
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner
NEW ORLEANS -- Adding an investigational protease inhibitor for hepatitis C virus (HCV) to standard treatment induced rapid and sustained virologic responses in many patients with poor responses to standard therapy alone, researchers said here.
In an open-label extension study, most patients with inadequate or no responses, or who showed renewed viral activity after an initial response to pegylated interferon and ribavirin, succeeded in achieving so-called sustained virologic responses to a second course of treatment that included telaprevir, reported Andrew Muir, MD, of Duke University.
Another analysis of one of these trials also showed that, among patients with inadequate initial responses to the standard regimen, even those with risk factors predicting especially poor responses did well when telaprevir was added, Muir said.
He presented the findings in two sessions here at Digestive Disease Week and at a press conference.
Telaprevir is one of two HCV protease inhibitors now in development, the other being boceprevir. These drugs are widely expected to be the first direct antiviral drugs made available for HCV, with FDA approval possible in 2011.
One of the studies Muir presented involved 117 participants in three earlier trials in the PROVE series who were in the standard-therapy arms and failed to show sustained virologic responses. They were categorized by the type of poor response: null responders (those with little or no change in viral loads), partial responders (initial decrease of at least two logs in HCV RNA but virus still detectable at week 24), and relapses and breakthroughs.
These patients underwent a second round of treatment with PEG-interferon and ribavirin at standard doses with the addition of telaprevir at 750 mg every eight hours. All three drugs were given for 12 weeks, with interferon and ribavirin continued for an additional 12 weeks.
Patients not showing complete responses at week 24 received an additional 24 weeks of interferon and ribavirin.
Muir said more than half of patients, 59%, had sustained virologic responses to the 12 weeks of telaprevir and 24 weeks of standard therapy.
Among the 35 who ended up taking interferon and ribavirin for the full 48 weeks, 52% had sustained responses.
The shorter regimen was not very effective in the subgroup with null responses to standard therapy during the PROVE studies. Only 13% of these patients developed sustained virologic responses during the first 24 weeks. But 57% of those who stayed on therapy for 48 weeks achieved sustained responses, according to Muir.
Among the other subgroups, response rates to the 24-week regimen ranged from 60% to 92%. Only seven patients in those subgroups received 48 weeks of treatment, of whom two obtained sustained responses.
The other study presented by Muir was a post hoc subgroup analysis of responses in "difficult to cure" patients in one of the earlier trials, PROVE3. These were patients who had one or more risk factors previously known to predict poor responses to interferon and ribavirin.
These included:
- HCV genotype 1
- Age
- High baseline viral load
- Male gender
- Obesity
- Bridging fibrosis in the liver
PROVE3 was a randomized trial that assigned patients to interferon and ribavirin at standard doses for 48 weeks with or without 12 weeks of telaprevir, or to 24 weeks of the standard therapy plus 12 weeks of telaprevir. There was also a fourth arm, combining telaprevir and interferon without ribavirin, that was excluded from the new analysis.
Muir reported that, in each major risk-factor group, patients in both telaprevir arms did far better than those receiving the standard therapy alone.
Sustained viral responses were achieved in 44% to 61% of patients receiving telaprevir, compared with 10% to 15% of those receiving only the standard regimen (P<0.0001 for all comparisons), for the following subgroups: males, those older than 50, those with body mass index values of 25 to 30, those with BMI over 30, those with initial viral loads of more than 800,000 IU/mL, and those with bridging fibrosis or cirrhosis.
Patients with the risk factor associated with the worst outcomes -- those with no response at all to initial interferon and ribavirin treatment -- also did better with telaprevir, with 38% obtaining sustained responses.
Multivariate analysis indicated that adding telaprevir increased the chances of achieving a sustained response by nearly nine-fold (odds ratio 8.7, 95% CI 4.6 to 16.7).
In his presentations here, Muir spent little time addressing adverse effects. However, earlier reports from the PROVE series indicated that anemia and skin rashes and pruritus were relatively common with telaprevir.
Philip Schoenfeld, MD, of the University of Michigan in Ann Arbor, who moderated the press conference where Muir spoke, said the results with HCV protease inhibitors have been highly encouraging.
"These agents offer the opportunity for a revolution in the treatment of hepatitis C virus patients, achieving successful eradication of the virus in substantially more patients," he said.
In particular, Schoenfeld added, boceprevir and telaprevir offer "new hope for patients who have failed conventional therapies."
Primary source: Digestive Disease Week
Source reference:
Muir A, et al "Final results of a rollover study assessing telaprevir in combination with peginterferon alfa-2a and ribavirin in chronic HCV patients with well-characterized null response, partial response, viral breakthrough, or relapse after prior PR treatment" DDW 2010; Abstract 311.
Additional source: Digestive Disease Week
Source reference:
Muir A, et al "Improved sustained virologic response (SVR) in "difficult-to-cure" patients treated with telaprevir (T) in combination with peginterferon alfa-2a (P) and ribavirin (R): An analysis from the PROVE3 study" DDW 2010; Abstract T2002
Source
Also See: DDW: New Drug Treatments Hold Promise for Hepatitis C Patients
June 20, 2010
DDW: Researchers Make Advances In Understanding Causes, Treatments And Outcomes Of Liver Disease
Health Outcomes Explored at DDW® 2010
NEW ORLEANS, LA (May 2, 2010) – Non-alcoholic fatty liver disease (NAFLD), which may soon be the leading indication for liver transplant, is found to be significantly associated with worse transplant outcomes. In addition, a new tool for diagnosing NAFLD represents an alternative to liver biopsy, which is more expensive and prone to complications, and ultrasound and alfafeprotein blood test screening are an effective alternative to CT scan and MRI for patients with cirrhosis at high risk for hepatocellular cancer. These are among the research findings being presented at Digestive Disease Week® (DDW®) 2010. DDW is the largest international gathering of physicians and researchers in the field of gastroenterology, hepatology, endoscopy and gastrointestinal surgery.
“NAFLD is a growing concern in the U.S. and the research presented here gives us a better understanding of its influence on transplant outcomes as well as alternatives in diagnosing the condition,” said Frank Anania, MD, AGAF, Emory University School of Medicine, associate professor of medicine, director of hepatology.
The Influence of NAFLD and Its Associated Comorbidities on Liver Transplant Outcomes (Abstract #S1858)
NAFLD is significantly associated with worse transplant outcomes (death and graft failure) within the first 30 days after transplant, according to new research from the University of North Carolina (UNC), Chapel Hill.
NAFLD is a rising epidemic in the U.S., fueled in part by the dual epidemics of obesity and diabetes. As NAFLD increases in incidence and prevalence, researchers say they expect it to become the leading indication for liver transplantation in the next two decades. Unfortunately, the same risk factors for NAFLD — diabetes, obesity, high blood pressure and high cholesterol — are also risk factors for heart disease.
Researchers used a retrospective cohort study design to analyze 118 liver transplants over a three-year period. Besides NAFLD, diabetes was also associated with worse outcome and having poorer survival at three years after transplant. High blood pressure, high cholesterol and obesity were not independently associated with death or graft failure.
The study builds on previous research published in 2009, which reached similar conclusions. However, the group at UNC was able to use a stronger study design with a more extensive accounting of donor, operative and patient characteristics.
"Patients with NAFLD may need a more thorough pre-operative assessment prior to listing for liver transplant," said A. Sidney Barritt IV, MD, MSCR, fellow in advanced hepatology and liver transplant, UNC, Chapel Hill. "Future work should determine strategies to decrease perioperative mortality among patients with NAFLD."
That said, the study is a single center experience with a relatively small number of patients, so the researchers are actively building a consortium of transplant centers to research liver transplant outcomes. They aim to repeat a similar study on a much larger scale to validate their findings.
Dr. Barritt said despite the findings, patients with NAFLD will continue to be considered for liver transplant. "Our intent is to find ways to improve transplant outcomes for this population and to ensure that liver transplantation remains a viable, cost-effective intervention for all people with liver disease," he said.
Dr. Barritt will present these data on Sunday, May 2 at 8 a.m. CT in Hall F, Ernest N. Morial Convention Center.
Can the NAFLD Fibrosis Score be used as a Prognostic Predictor for Poor Outcomes of NAFLD Patients? (Abstract #S1848)
Researchers from Chulalongkorn University, Bangkok, Thailand, and the Mayo Clinic have developed a scoring system that for the first time appears to predict liver complications or even death in patients with NAFLD.
NAFLD is one of the most common causes of chronic liver disease and its prevalence is rising, in part because of the increasing incidence of obesity. Liver biopsy is widely considered the gold standard to diagnose the severity of NAFLD, but it is expensive, invasive and associated with a number of complications. Currently, there are no medications to treat fatty liver effectively.
To address this issue, researchers developed a simple tool, the "NAFLD fibrosis score," a composite score of variables, including medical history, age, high blood sugar and body mass index, as well as variables from blood tests including platelet count, albumin and AST/ALT ratio (liver tests). These factors were found to be an indicator for separating NAFLD patients with and without advanced or severe liver fibrosis at the initial NAFLD diagnosis. Participants were predominantly middle-aged (47 years; range 21 to 86 years), were white (95 percent) and 44 percent were male. Obesity was present in 73 percent of the population. History of high blood sugar and high blood pressure were found in 16 percent and 41 percent respectively.
Researchers used data from a cohort study of fatty liver patients diagnosed from 1980 to 2000 including 302 patients with an average follow-up of 12 years and found: the NAFLD fibrosis score change per year in patients who died was significantly higher than in those who survived; intermediate to high probability of advanced liver fibrosis assessed by NAFLD fibrosis score were found in 40 percent of patients; and higher NAFLD fibrosis score at baseline, less often use of metformin and higher creatinine at the end of follow up significantly predicted death or development of liver complication in patients with fatty liver. Results also showed that 40 percent of patients with fatty liver were in an intermediate or high probability of advanced liver fibrosis at baseline and most of them (94 percent) were still in advanced liver fibrosis group at the end of follow up.
"This quantitative scoring system should be calculated for all patients with NAFLD at initial consultation to estimate the probability of advanced liver fibrosis without additional costs," said Sombat Treeprasertsuk, MD, a gastroenterologist from Chulalongkorn University, Bangkok, Thailand, and the Mayo Clinic, Rochester, MN. "Once providers identify patients with fatty liver who have a high score or high risk of poor outcomes, they can set up a customized follow-up regimen for these patients." The test can then be recalculated to monitor progress.
Dr. Treeprasertsuk cautioned that when the tool shows a high risk of death or development of liver complications, be mindful that every diagnostic test has a true positive or a false positive result. He also encouraged people to improve their liver health through lifestyle, diet and regular exercise.
Dr. Treeprasertsuk will present these data on Sunday, May 2 at 8 a.m. CT in Hall F, Ernest N. Morial Convention Center.
Use of Ultrasound as the Initial Imaging Exam for Hepatocellular Carcinoma in High Risk Population (Abstract #S1278)
Patients with cirrhosis who are at high risk for developing heptatocellular cancer (HCC) can be effectively screened via ultrasound and alfa fetoprotein (AFP) blood test screening, rather than more costly CT or MRI scans. Researchers from the University of Texas Medical Branch at Galveston found that results from ultrasound and AFP screenings were accurate in detecting HCC. High levels of AFP are considered a biomarker for HCC.
To test the accuracy and sensitivity of standard monitoring procedures for patients with cirrhosis for the development of HCC, researchers retrospectively compared standard monitoring of ultrasound with AFP screening to subsequent results from CT or MRI scans performed within six months of the initial screening. Researchers found ultrasound alone was 99 percent specific and 76 percent sensitive in the detection of HCC. When elevated AFP was screened, specificity increased to 100 percent and the sensitivity to 87.5 percent.
"These findings emphasize the importance of using ultrasound, together with alfa fetoprotein, as the initial screening protocol, and provide a road map for when additional screening procedures, like CT and MRI scans should be undertaken," said Roger D. Soloway, MD, Marie B. Gale Centennial professor of internal medicine, University of Texas Medical Branch, gastroenterology, hepatology and nutrition division, department of internal medicine. "This data can lead to decreased use of CT without sacrificing detection rate significantly."
This retrospective analysis of demographic and laboratory data included 160 cases in which an initial ultrasound was performed followed by a CT or MRI within six months; this group included 34 cases of suspected HCC. From these suspected cases, 26 patients were correctly identified as having HCC by ultrasound. In eight cases in which ultrasound was falsely negative and CT found a lesion, the average AFP level was 32,325 ng/mL. In the 125 patients with a true negative ultrasound, the average AFP was 17.14 ng/mL. This group had only 12 patients, with an AFP greater than 20 ng/mL, and only one who had an AFP greater than 400 ng/mL.
For the entire population of patients, the positive predictive value of ultrasound for detecting HCC was 96.3 percent, while the negative predictive value was 94 percent. Only two patients had a negative ultrasound, with a normal AFP level and still had HCC.
These findings demonstrate that even with high risk patients, if ultrasound does not show a focal lesion and the AFP is normal, these standard monitoring tests should be repeated in six months. If the ultrasound does not show a focal lesion but the AFP is elevated (> 20 ng/mL), a CT and AFP should be obtained in three months as follow up.
"Ultrasound can eliminate more expensive imaging studies until confirmation is necessary, helping to reduce the overall cost of medical monitoring for patients in heptatocellular cancer screening populations," said Dr. Soloway. He cautioned that, while ultrasound is an effective screening for this group, it is not as sensitive as CT for detecting HCC.
Dr. Soloway will present these data on Sunday, May 2 at 8 a.m.. CT in Hall F, Ernest N. Morial Convention Center.
The Significance of Buprenorphine Use and Adherence in AntiHCV Treatment Outcome in Drug Users (Abstract # M1883)
A new study shows successful treatment of intravenous drug users (IVDUs) with hepatitis C virus (HCV) when treated concurrently with anti-viral and opioid substitution therapies. Intravenous drug use is a main cause of HCV transmission in Western countries, and IVDU patients with HCV are generally treated on a case-by-case basis according to current guidelines because of concerns regarding low adherence and response rates in treatment.
Investigators from The Greek Organisation Against Drugs (OKANA) and the Medical Schools of Athens and Thessaloniki evaluated common anti-HCV treatment outcomes in IVDUs receiving methadone or buprenorphine. Patients were evaluated on their adherence to treatment and the sustained virologic response (SVR) to medication, meaning no HCV RNA was detectectable by blood tests for an extended period of time following treatment.
From 2002 to 2008, 95 IVDUs with chronic HCV infection started antiviral treatment. All of them were treated with opioid-substitution therapy, 46 with methadone and 49 with buprenorphine. More than 82 percent of patients completed the treatment schedule, while seven patients discontinued treatment due to side effects and nine patients due to their own decision. SVR was observed in 66.3 percent of patients with six months post-treatment data available; 15 patients were non-responders or relapsed and 17 had not completed the treatment schedule or were lost to follow up.
SVR was higher in patients who were adherent to treatment (adherent versus discontinuation side effects versus discontinuation by own decision: 77.9 percent versus 28.6 percent versus 0 percent). Buprenorphine was also found to be associated with higher rates of fulfilling treatment schedule compared to methadone (8.1 percent discontinuation versus 27.3 percent).
"Our research demonstrates that patients with hepatitis C virus infection can be effectively treated as long as they are kept adherent," said Olga Anagnostou, MD, OKANA. "Intravenous drug users with hepatitis C infection should not be excluded from treatment — especially when they are on substitution treatment."
The results of the Greek study suggest the reconsideration of eligibility criteria for initiation of an anti-viral treatment in IVDUs and revealed the crucial role that buprenorphine may play on improving adherence and response rates.
Dr. Anagnostou will present these data on Monday, May 3 at 8 a.m. CT in Ballroom C, Ernest N. Morial Convention Center.
http://www.ddw.org/wmspage.cfm?parm1=912
NEW ORLEANS, LA (May 2, 2010) – Non-alcoholic fatty liver disease (NAFLD), which may soon be the leading indication for liver transplant, is found to be significantly associated with worse transplant outcomes. In addition, a new tool for diagnosing NAFLD represents an alternative to liver biopsy, which is more expensive and prone to complications, and ultrasound and alfafeprotein blood test screening are an effective alternative to CT scan and MRI for patients with cirrhosis at high risk for hepatocellular cancer. These are among the research findings being presented at Digestive Disease Week® (DDW®) 2010. DDW is the largest international gathering of physicians and researchers in the field of gastroenterology, hepatology, endoscopy and gastrointestinal surgery.
“NAFLD is a growing concern in the U.S. and the research presented here gives us a better understanding of its influence on transplant outcomes as well as alternatives in diagnosing the condition,” said Frank Anania, MD, AGAF, Emory University School of Medicine, associate professor of medicine, director of hepatology.
The Influence of NAFLD and Its Associated Comorbidities on Liver Transplant Outcomes (Abstract #S1858)
NAFLD is significantly associated with worse transplant outcomes (death and graft failure) within the first 30 days after transplant, according to new research from the University of North Carolina (UNC), Chapel Hill.
NAFLD is a rising epidemic in the U.S., fueled in part by the dual epidemics of obesity and diabetes. As NAFLD increases in incidence and prevalence, researchers say they expect it to become the leading indication for liver transplantation in the next two decades. Unfortunately, the same risk factors for NAFLD — diabetes, obesity, high blood pressure and high cholesterol — are also risk factors for heart disease.
Researchers used a retrospective cohort study design to analyze 118 liver transplants over a three-year period. Besides NAFLD, diabetes was also associated with worse outcome and having poorer survival at three years after transplant. High blood pressure, high cholesterol and obesity were not independently associated with death or graft failure.
The study builds on previous research published in 2009, which reached similar conclusions. However, the group at UNC was able to use a stronger study design with a more extensive accounting of donor, operative and patient characteristics.
"Patients with NAFLD may need a more thorough pre-operative assessment prior to listing for liver transplant," said A. Sidney Barritt IV, MD, MSCR, fellow in advanced hepatology and liver transplant, UNC, Chapel Hill. "Future work should determine strategies to decrease perioperative mortality among patients with NAFLD."
That said, the study is a single center experience with a relatively small number of patients, so the researchers are actively building a consortium of transplant centers to research liver transplant outcomes. They aim to repeat a similar study on a much larger scale to validate their findings.
Dr. Barritt said despite the findings, patients with NAFLD will continue to be considered for liver transplant. "Our intent is to find ways to improve transplant outcomes for this population and to ensure that liver transplantation remains a viable, cost-effective intervention for all people with liver disease," he said.
Dr. Barritt will present these data on Sunday, May 2 at 8 a.m. CT in Hall F, Ernest N. Morial Convention Center.
Can the NAFLD Fibrosis Score be used as a Prognostic Predictor for Poor Outcomes of NAFLD Patients? (Abstract #S1848)
Researchers from Chulalongkorn University, Bangkok, Thailand, and the Mayo Clinic have developed a scoring system that for the first time appears to predict liver complications or even death in patients with NAFLD.
NAFLD is one of the most common causes of chronic liver disease and its prevalence is rising, in part because of the increasing incidence of obesity. Liver biopsy is widely considered the gold standard to diagnose the severity of NAFLD, but it is expensive, invasive and associated with a number of complications. Currently, there are no medications to treat fatty liver effectively.
To address this issue, researchers developed a simple tool, the "NAFLD fibrosis score," a composite score of variables, including medical history, age, high blood sugar and body mass index, as well as variables from blood tests including platelet count, albumin and AST/ALT ratio (liver tests). These factors were found to be an indicator for separating NAFLD patients with and without advanced or severe liver fibrosis at the initial NAFLD diagnosis. Participants were predominantly middle-aged (47 years; range 21 to 86 years), were white (95 percent) and 44 percent were male. Obesity was present in 73 percent of the population. History of high blood sugar and high blood pressure were found in 16 percent and 41 percent respectively.
Researchers used data from a cohort study of fatty liver patients diagnosed from 1980 to 2000 including 302 patients with an average follow-up of 12 years and found: the NAFLD fibrosis score change per year in patients who died was significantly higher than in those who survived; intermediate to high probability of advanced liver fibrosis assessed by NAFLD fibrosis score were found in 40 percent of patients; and higher NAFLD fibrosis score at baseline, less often use of metformin and higher creatinine at the end of follow up significantly predicted death or development of liver complication in patients with fatty liver. Results also showed that 40 percent of patients with fatty liver were in an intermediate or high probability of advanced liver fibrosis at baseline and most of them (94 percent) were still in advanced liver fibrosis group at the end of follow up.
"This quantitative scoring system should be calculated for all patients with NAFLD at initial consultation to estimate the probability of advanced liver fibrosis without additional costs," said Sombat Treeprasertsuk, MD, a gastroenterologist from Chulalongkorn University, Bangkok, Thailand, and the Mayo Clinic, Rochester, MN. "Once providers identify patients with fatty liver who have a high score or high risk of poor outcomes, they can set up a customized follow-up regimen for these patients." The test can then be recalculated to monitor progress.
Dr. Treeprasertsuk cautioned that when the tool shows a high risk of death or development of liver complications, be mindful that every diagnostic test has a true positive or a false positive result. He also encouraged people to improve their liver health through lifestyle, diet and regular exercise.
Dr. Treeprasertsuk will present these data on Sunday, May 2 at 8 a.m. CT in Hall F, Ernest N. Morial Convention Center.
Use of Ultrasound as the Initial Imaging Exam for Hepatocellular Carcinoma in High Risk Population (Abstract #S1278)
Patients with cirrhosis who are at high risk for developing heptatocellular cancer (HCC) can be effectively screened via ultrasound and alfa fetoprotein (AFP) blood test screening, rather than more costly CT or MRI scans. Researchers from the University of Texas Medical Branch at Galveston found that results from ultrasound and AFP screenings were accurate in detecting HCC. High levels of AFP are considered a biomarker for HCC.
To test the accuracy and sensitivity of standard monitoring procedures for patients with cirrhosis for the development of HCC, researchers retrospectively compared standard monitoring of ultrasound with AFP screening to subsequent results from CT or MRI scans performed within six months of the initial screening. Researchers found ultrasound alone was 99 percent specific and 76 percent sensitive in the detection of HCC. When elevated AFP was screened, specificity increased to 100 percent and the sensitivity to 87.5 percent.
"These findings emphasize the importance of using ultrasound, together with alfa fetoprotein, as the initial screening protocol, and provide a road map for when additional screening procedures, like CT and MRI scans should be undertaken," said Roger D. Soloway, MD, Marie B. Gale Centennial professor of internal medicine, University of Texas Medical Branch, gastroenterology, hepatology and nutrition division, department of internal medicine. "This data can lead to decreased use of CT without sacrificing detection rate significantly."
This retrospective analysis of demographic and laboratory data included 160 cases in which an initial ultrasound was performed followed by a CT or MRI within six months; this group included 34 cases of suspected HCC. From these suspected cases, 26 patients were correctly identified as having HCC by ultrasound. In eight cases in which ultrasound was falsely negative and CT found a lesion, the average AFP level was 32,325 ng/mL. In the 125 patients with a true negative ultrasound, the average AFP was 17.14 ng/mL. This group had only 12 patients, with an AFP greater than 20 ng/mL, and only one who had an AFP greater than 400 ng/mL.
For the entire population of patients, the positive predictive value of ultrasound for detecting HCC was 96.3 percent, while the negative predictive value was 94 percent. Only two patients had a negative ultrasound, with a normal AFP level and still had HCC.
These findings demonstrate that even with high risk patients, if ultrasound does not show a focal lesion and the AFP is normal, these standard monitoring tests should be repeated in six months. If the ultrasound does not show a focal lesion but the AFP is elevated (> 20 ng/mL), a CT and AFP should be obtained in three months as follow up.
"Ultrasound can eliminate more expensive imaging studies until confirmation is necessary, helping to reduce the overall cost of medical monitoring for patients in heptatocellular cancer screening populations," said Dr. Soloway. He cautioned that, while ultrasound is an effective screening for this group, it is not as sensitive as CT for detecting HCC.
Dr. Soloway will present these data on Sunday, May 2 at 8 a.m.. CT in Hall F, Ernest N. Morial Convention Center.
The Significance of Buprenorphine Use and Adherence in AntiHCV Treatment Outcome in Drug Users (Abstract # M1883)
A new study shows successful treatment of intravenous drug users (IVDUs) with hepatitis C virus (HCV) when treated concurrently with anti-viral and opioid substitution therapies. Intravenous drug use is a main cause of HCV transmission in Western countries, and IVDU patients with HCV are generally treated on a case-by-case basis according to current guidelines because of concerns regarding low adherence and response rates in treatment.
Investigators from The Greek Organisation Against Drugs (OKANA) and the Medical Schools of Athens and Thessaloniki evaluated common anti-HCV treatment outcomes in IVDUs receiving methadone or buprenorphine. Patients were evaluated on their adherence to treatment and the sustained virologic response (SVR) to medication, meaning no HCV RNA was detectectable by blood tests for an extended period of time following treatment.
From 2002 to 2008, 95 IVDUs with chronic HCV infection started antiviral treatment. All of them were treated with opioid-substitution therapy, 46 with methadone and 49 with buprenorphine. More than 82 percent of patients completed the treatment schedule, while seven patients discontinued treatment due to side effects and nine patients due to their own decision. SVR was observed in 66.3 percent of patients with six months post-treatment data available; 15 patients were non-responders or relapsed and 17 had not completed the treatment schedule or were lost to follow up.
SVR was higher in patients who were adherent to treatment (adherent versus discontinuation side effects versus discontinuation by own decision: 77.9 percent versus 28.6 percent versus 0 percent). Buprenorphine was also found to be associated with higher rates of fulfilling treatment schedule compared to methadone (8.1 percent discontinuation versus 27.3 percent).
"Our research demonstrates that patients with hepatitis C virus infection can be effectively treated as long as they are kept adherent," said Olga Anagnostou, MD, OKANA. "Intravenous drug users with hepatitis C infection should not be excluded from treatment — especially when they are on substitution treatment."
The results of the Greek study suggest the reconsideration of eligibility criteria for initiation of an anti-viral treatment in IVDUs and revealed the crucial role that buprenorphine may play on improving adherence and response rates.
Dr. Anagnostou will present these data on Monday, May 3 at 8 a.m. CT in Ballroom C, Ernest N. Morial Convention Center.
http://www.ddw.org/wmspage.cfm?parm1=912
DDW: New Drug Treatments Hold Promise for Hepatitis C Patients
Dr. Andrew Muir was my Hepatologist at Duke who
treated me in 2005. When all other Drs told me I could never do
treatment again, he gave me the chance to retreat.
treated me in 2005. When all other Drs told me I could never do
treatment again, he gave me the chance to retreat.
I have been SVR now since May 2006.
2010 Press Releases
Health Outcomes Explored at DDW® 2010
NEW ORLEANS, LA (May 4, 2010) – Research being presented at Digestive Disease Week® (DDW®) shows that using telaprevir in the treatment regimen for hepatitis C virus (HCV) is highly effective, particularly in difficult-to-treat cases. Further studies show that aspirin may be a factor in the development of inflammatory bowel disease. DDW is the largest international gathering of physicians and researchers in the field of gastroenterology, hepatology, endoscopy and gastrointestinal surgery.
"Treatment for hepatitis C has historically been challenging, with available treatment options being uncomfortable for the patient and sometimes ineffective, but the science presented here offers hope for the patients living with the infection and the doctors who treat them," said Philip S. Schoenfeld, MD, MSEd, MSc (Epi), associate professor of medicine University of Michigan School of Medicine. "Inflammatory bowel disease, including Crohn’s disease, has been historically difficult to treat, partly because we’re still learning how the disease occurs. These data will help us better understand this debilitating disease."
Final Results of A Rollover Study Assessing Telaprevir in Combination with Peginterferon Alfa-2A and Ribavirin in Chronic Hepatitis C Patients with Well-Characterized Null Response, Partial Response, Virtual Breakthrough, or Relapse After Prior PR Treatment (Abstract #311)
Researchers at Duke Clinical Research Institute found that patients who had not improved with standard HCV treatment significantly improved response rates when telaprevir was added to the standard treatment regimen.
A previous study had suggested that patients who had failed prior treatments benefited from telaprevir, but the Duke researchers did not have records from these patients to know the full details of their previous treatment. In this study, researchers studied patients from previous telaprevir trials during which patients received standard treatment with peginterferon and ribavirin, but placebo instead of telaprevir, a drug frequently used in the treatment of HCV.
Researchers looked at 117 patients, all of whom received treatment with the combination of pegylated interferon alfa, ribavirin and telaprevir. All patients received 12 weeks of the triple combination and then 12 to 36 more weeks of pegylated interferon alfa and ribavirin.
Telaprevir was discontinued after 12 weeks, and the patients continued for 12 or 36 more weeks of peginterferon alfa and ribavirin. Results showed that null responders — patients who did not respond to previous treatment (<1-log10 decrease in HCV RNA at week four or <2-log10 at week 12) — needed 48 weeks of treatment, but 57 percent of null responders were cured with this regimen.
The other groups received the 12 weeks of triple combination therapy plus 12 more weeks of peginterferon alfa and ribavirin. For patients who were partial responders to previous therapy, 60 percent were cured with the triple combination. For patients who relapsed with previous therapy, 92 percent were cured with the triple combination.
"The results seen in this trial were encouraging for all patient groups studied," said Andrew J. Muir, MD, director of GI/hepatology research at Duke Clinical Research Institute, Duke University. "This study is yet another indication that telaprevir is consistently showing potential efficacy as a new treatment option for patients who have failed treatment, but also reinforces the additional side effects that come with adding this drug to standard treatments."
The study was funded by Vertex Pharmaceuticals, which is developing telaprevir.
Dr. Muir will present these data on Monday, May 3 at 9 a.m. CT in 383-385, Ernest N. Morial Convention Center.
Improved Sustained Virologic Response (SVR) in “Difficult to Cure” Patients Treated with Telaprevir (T) in Combination with Peginterferon Alfa-2a (P) and Ribavirin (R): An Analysis from the PROVE3 Study (Abstract #T2002)
A new study from Duke Clinical Research Institute shows that telaprevir is effective in difficult-to-treat populations with HCV. Researchers focused on populations traditionally referred to as difficult to treat, including patients with a high viral load (very severe infection), cirrhosis, older or obese patients, or African Americans, and found they all experienced improved response rates. The findings are significant because previous studies have not achieved such high response rates.
This research was a secondary analysis of a large prospective, randomized, controlled trial, PROVE3, which enrolled patients who did not respond to previous standard treatment with peginterferon alfa and ribavirin. Patients (453) were assigned to one of four treatment approaches, which included varying combinations of telaprevir in combination with peginterferon alfa and ribavirin, as well as peginterferon alfa, ribavirin and placebo.
"These findings, if confirmed in larger phase III studies, could provide a meaningful treatment option for clinicians to consider when dealing with patients who have failed an initial standard of care treatment regimen," said Andrew J. Muir, MD, director of GI/hepatology research at Duke Clinical Research Institute, Duke University.
Dr. Muir cautioned that this study is a secondary analysis, and the numbers in each subgroup are small; they need to be further confirmed in larger trials. The study was funded by Vertex Pharmaceuticals, which is developing telaprevir.
Dr. Muir will present these data on Tuesday, May 4 at from 8:00 a.m. CT in Hall F, Ernest N. Morial Convention Center.
http://www.ddw.org/wmspage.cfm?parm1=920
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