Monday, December 16, 2013
'Stop wasting money on vitamin and mineral supplements'
Video Source
Annals of Internal Medicine - Vitamin supplements a waste of money?
1. Physicians urge, 'stop wasting money on vitamin and mineral supplements'
Editorialists responding to three articles on vitamin and mineral supplementation being published in Annals of Internal Medicine urge U.S. adults to stop wasting their money on dietary supplements. The authors cite the large body of accumulated evidence showing that most multivitamin supplements are ineffective, and some may cause harm. The message is simple, the authors write. Most supplements do not prevent chronic disease or death, their use is not justified, and they should be avoided.
Summaries of two of the articles appear below. The third article was previously published in Annals of Internal Medicine as an early online release. The review by the United States Preventive Services Task Force found insufficient evidence that multivitamins prevent cancer, cardiovascular disease, or death.
2. Long-term multivitamin use does not preserve cognitive function in men
A substudy of a large, randomized, placebo-controlled trial being published in Annals of Internal Medicine shows that long-term use of a daily multivitamin did nothing to slow cognitive decline among men 65 and older. Multivitamins are the most commonly used dietary supplements in the United States. A typical daily multivitamin contains a combination of nutrients, such as vitamins A, C, E, β-carotene and B vitamins, thought to have properties that could help prevent cognitive decline. However, their benefit in preventing age-related cognitive decline is unclear. Researchers assigned 5,947 male physicians aged 65 and older to take either a daily multivitamin or placebo for 12 years. After an initial cognitive assessment, the men were tested for cognitive function and verbal memory via telephone interview three additional times at approximately two, six, and 10 years. The researchers saw no difference in cognitive function between the multivitamin and placebo groups, concluding that there is no benefit for taking a daily multivitamin to prevent cognitive decline.
3. High doses of multivitamins and minerals do not protect against cardiovascular events following myocardial infarction
Taking high doses of multivitamins and minerals does not protect against secondary cardiovascular events in stable patients receiving appropriate care after myocardial infarction (MI), according to a study being published in Annals of Internal Medicine. Researchers randomly assigned 1,708 patients aged 50 years or older who had MI at least six weeks earlier and had serum creatinine levels of 176.8 µmol/L (2.0 mg/dL) or less to take either an oral 28 component high-dose multivitamin and multimineral mixture or placebo. Patient records were reviewed to determine time to death, recurrent MI, stroke, coronary revascularization, or hospitalization for angina. While the multivitamin and mineral regimen was not harmful, it did not seem to reduce cardiovascular events in patients receiving appropriate, evidence-based medical therapy following MI.
Source: American College of Physicians
The Changing Treatment Armamentarium for HCV - From Today to 2016
The Changing Treatment Armamentarium for HCV:
From Today to 2016
Release Date: December 12, 2013
Hello folks,
If you have time to spare during this busy holiday jump over to Clinical Care Options (CCO) for an in-depth review of approved and future HCV drugs, presented by Nezam H. Afdhal, MD, FRCPI.
**Free registration is required
The online activity explores the most critical areas of HCV research, topics include;
The Goal of Combination Regimens
Simeprevir and Faldaprevir: Second-Generation PI-Based Therapy
Novel Classes With Peginterferon/Ribavirin in Genotype 1 HCV
The Advent of All-Oral HCV Therapy
Three- and Four-Drug Oral Regimens: Pros and Cons
Can Two-Drug Regimens Be Effective?
Treatment of Patients With HCV Genotype 2 or 3 Infection
Summary: Predicting the Future of HCV Treatment
Excerpt: The Advent of All-Oral HCV Therapy
Ideally, treatment approaches for HCV infection would comprise all-oral regimens. Many studies are currently evaluating regimens that comprise different combinations of oral agents. Many of these regimens include ribavirin, but given the hematologic toxicities of this agent, future HCV regimens will likely consist of combinations of oral DAAs.
NS5B PIs are the class of DAAs with which clinicians currently have the greatest experience, albeit predominantly in combination with peginterferon/ribavirin. The approval of telaprevir and boceprevir in 2011 represents the first recent advance in HCV therapy. In addition, the next-generation PIs faldaprevir and simeprevir (the latter approved in November 2013) are in advanced clinical development. These agents have high efficacy, with ≥ 4 log reductions in HCV RNA levels.
However, this class of drugs predominantly targets genotype 1 only (although some of them show efficacy against other genotypes). In addition, PIs have relatively low barriers to resistance.
NS5A inhibitors (eg, daclatasvir and ledipasvir) feature efficacy, genotype specificity, and resistance barriers that are similar to the PIs. However, the nucleotide NS5B polymerase inhibitors, such as sofosbuvir, offer good efficacy with the advantages of pangenotypic activity and high barriers to resistance; in fact, there has been almost no resistance reported in patients who have been treated with sofosbuvir. By contrast, the NS5B nonnucleoside inhibitors provide the weakest efficacy, are very genotype specific, and have an extremely low barrier to resistance; however, they may retain some utility in combination regimens despite these shortcomings.
The class of cyclophilin inhibitors includes oral interferon inducers and other host-targeting agents. The strengths of these drugs include their pangenotypic activity and high resistance barrier. Cyclophilin inhibitors that are currently in development include alisporivir and Debio 025, although the former is on clinical hold. The usefulness of these agents in HCV treatment remains to be determined.
In December 2013, the first all-oral regimen for HCV, sofosbuvir plus ribavirin, received Food and Drug Administration approval for treatment of patients infected with HCV genotype 2 or genotype 3. In 2014 and 2015, other all-oral HCV treatment regimens may be approved. Many therapeutic combinations are possible, but with the approval of both sofosbuvir and simeprevir, there is likely to be interest in exploring the off-label combination of these agents, in light of promising preliminary data. By 2016, truly pangenotypic all-oral therapies for HCV infection should be available; the most significant advance will be the development of pangenotypic NS3/4A PIs and NS5A inhibitors that have higher barriers to resistance. Such regimens should allow patients with all HCV genotypes and subtypes to be treated successfully.
Click here to begin activity
Hepatitis C: Boehringer Ingelheim’s faldaprevir effective in patients with common drug-resistant viral variant
Hepatitis C: Phase III data show Boehringer Ingelheim’s faldaprevir* is effective even in patients with common drug-resistant viral variant
INGELHEIM, Germany--(BUSINESS WIRE)-- Data show that Boehringer Ingelheim’s second-generation protease inhibitor faldaprevir*, when used in combination with pegylated interferon and ribavirin, was effective even with the presence of naturally-occurring mutant variants of the hepatitis C virus (HCV), such as the NS3 Q80K polymorphism. The Q80K mutant was detected in 23% (49/127, STARTVerso™1) and 40% (159/398, STARTVerso™2) of genotype-1a infected patients. Its presence was found to have no effect on the chances of viral cure (SVR12) in genotype-1 infected hepatitis C patients treated with faldaprevir* plus pegylated interferon and ribavirin.1 These data were presented last week at HEP DART 2013, taking place in Big Island, Hawaii.
“These data are encouraging as they demonstrate that HCV genotype-1 infected patients irrespective of the presence of the common HCV Q80K variant may benefit from faldaprevir*,” said Christoph Sarrazin, M.D., Professor of Medicine at the Johann Wolfgang Goethe University Hospital in Frankfurt, Germany. “In some parts of the world, the Q80K mutation is present in almost 50% of genotype-1a infected patients, who will potentially require additional screening prior to using some HCV protease inhibitors. With faldaprevir’s* efficacy against HCV Q80K, physicians should be able to avoid screening for this mutation prior to treatment of genotype-1a infected patients.”
The HCV NS3/4A protease is essential for viral replication and is a key target for direct acting antiviral (DAA) treatments such as faldaprevir*. The NS3 Q80K variant is the most commonly observed NS3 polymorphism in genotype-1a HCV and has been reported in up to 47% of genotype-1a infected patients. The variation in frequency is influenced by the geography, with the prevalence of Q80K being particularly high in the USA.4
Faldaprevir* is the core component of Boehringer Ingelheim’s investigational hepatitis C pipeline and is being studied in combinations both with and without interferon. Faldaprevir* was recently granted accelerated assessment by the European Medicines Agency. If approved by the European Commission, faldaprevir* could be available for marketing in the EU in the second half of 2014 as part of an interferon-based regimen. In addition, Boehringer Ingelheim aims to deliver one of the first interferon-free regimens for the treatment of hepatitis C infection. Pivotal Phase III HCVerso® data for the interferon-free regimen of faldaprevir*, deleobuvir* and ribavirin will be available in 2014.
Additional data from Boehringer Ingelheim at HEP DART
Data presented last week as part of the ‘oral abstract session II’ show a high rate of virologic response in patients treated with a 12 week all-oral combination of Boehringer Ingelheim’s faldaprevir* and deleobuvir* and Presidio’s PPI-668* with and without ribavirin.7 Results from the ongoing Phase II trial were recently presented at the 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD).
*Faldaprevir, deleobuvir and PPI-668 are investigational compounds and not yet approved. Their safety and efficacy have not yet been fully established.
The Boehringer Ingelheim NewsHome: An innovative resource for journalists
The Boehringer Ingelheim hepatitis C www.newshome.com is the one-stop-shop for clear, concise and easy to understand information about hepatitis C for media.
INGELHEIM, Germany--(BUSINESS WIRE)-- Data show that Boehringer Ingelheim’s second-generation protease inhibitor faldaprevir*, when used in combination with pegylated interferon and ribavirin, was effective even with the presence of naturally-occurring mutant variants of the hepatitis C virus (HCV), such as the NS3 Q80K polymorphism. The Q80K mutant was detected in 23% (49/127, STARTVerso™1) and 40% (159/398, STARTVerso™2) of genotype-1a infected patients. Its presence was found to have no effect on the chances of viral cure (SVR12) in genotype-1 infected hepatitis C patients treated with faldaprevir* plus pegylated interferon and ribavirin.1 These data were presented last week at HEP DART 2013, taking place in Big Island, Hawaii.
“These data are encouraging as they demonstrate that HCV genotype-1 infected patients irrespective of the presence of the common HCV Q80K variant may benefit from faldaprevir*,” said Christoph Sarrazin, M.D., Professor of Medicine at the Johann Wolfgang Goethe University Hospital in Frankfurt, Germany. “In some parts of the world, the Q80K mutation is present in almost 50% of genotype-1a infected patients, who will potentially require additional screening prior to using some HCV protease inhibitors. With faldaprevir’s* efficacy against HCV Q80K, physicians should be able to avoid screening for this mutation prior to treatment of genotype-1a infected patients.”
The HCV NS3/4A protease is essential for viral replication and is a key target for direct acting antiviral (DAA) treatments such as faldaprevir*. The NS3 Q80K variant is the most commonly observed NS3 polymorphism in genotype-1a HCV and has been reported in up to 47% of genotype-1a infected patients. The variation in frequency is influenced by the geography, with the prevalence of Q80K being particularly high in the USA.4
Faldaprevir* is the core component of Boehringer Ingelheim’s investigational hepatitis C pipeline and is being studied in combinations both with and without interferon. Faldaprevir* was recently granted accelerated assessment by the European Medicines Agency. If approved by the European Commission, faldaprevir* could be available for marketing in the EU in the second half of 2014 as part of an interferon-based regimen. In addition, Boehringer Ingelheim aims to deliver one of the first interferon-free regimens for the treatment of hepatitis C infection. Pivotal Phase III HCVerso® data for the interferon-free regimen of faldaprevir*, deleobuvir* and ribavirin will be available in 2014.
Additional data from Boehringer Ingelheim at HEP DART
Data presented last week as part of the ‘oral abstract session II’ show a high rate of virologic response in patients treated with a 12 week all-oral combination of Boehringer Ingelheim’s faldaprevir* and deleobuvir* and Presidio’s PPI-668* with and without ribavirin.7 Results from the ongoing Phase II trial were recently presented at the 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD).
*Faldaprevir, deleobuvir and PPI-668 are investigational compounds and not yet approved. Their safety and efficacy have not yet been fully established.
The Boehringer Ingelheim NewsHome: An innovative resource for journalists
The Boehringer Ingelheim hepatitis C www.newshome.com is the one-stop-shop for clear, concise and easy to understand information about hepatitis C for media.
Mapping HCV Infection in the Liver
Mapping HCV Infection in the Liver
Posted on December 16, 2013
by Kristine Novak, PhD, Science Editor
Using single-cell laser capture and high-resolution analysis, researchers show that hepatitis C virus (HCV) infects hepatocytes in the human liver in nonrandom clusters, whereas expression of anti-viral molecules is scattered among hepatocytes. The findings are presented in the December issue of Gastroenterology.
HCV predominantly infects hepatocytes, but most hepatocytes in the liver remain uninfected—HCV antigens have been observed to cluster. This suggests a localized mechanism of intra-hepatic propagation and control. Understanding this process could increase our understanding of infection and strategies for treatment.
Abraham J. Kandathil et al. analyzed liver samples from 4 patients with chronic HCV infection to estimate the proportion of infected hepatocytes and the amount of HCV RNA per cell using single-cell laser capture microdissection (LCM).
LCM unites light microscopy with a low-intensity ultraviolet laser, allowing researchers to ensnare enriched cellular material from tissue samples while preserving positional information, because the tissue is not homogenized. Kandathil et al. made improvements to the technique to increase its resolution, developing single-cell LCM, which allowed them to compare host and viral RNAs.
Studying viral replication in liver tissues from patients with chronic HCV infections, Kandathil et al. estimated the amount of HCV RNA per infected hepatocyte, to determine how the virus spreads in vivo and localize host cell expression of antiviral molecules.
The authors used their data to create a map of viral RNA in hepatocytes, which they called the viroscape. The viroscape shows hepatocytes containing narrow HCV replication peaks surrounded by broad regions with minimal or no HCV vRNA that resembled valleys (see video).
Kandathil et al. found that the proportion of HCV-infected hepatocytes per person ranged from 21% to 45%, and the level of viral RNA ranged from 1 to 50 IU/hepatocyte. However, infection was not random—the authors saw clusters of HCV-positive hepatocytes. These clusters in the hepatic viroscapes indicate cell-to-cell propagation of infection.
Kandathil et al. characterized the spatial association between intrahepatic HCV replication and innate immune signaling, and found that although expression of interferon-stimulated genes was sporadic, it was not specifically targeted toward or away from HCV-positive hepatocytes.
Clustering of HCV-infected hepatocytes did not appear to be caused by short-range immunologic control. IFITM3, an interferon-λ–induced protein that has direct antiviral effects against HCV in cell culture, did not appear to be directed specifically toward or away from infected hepatocytes (green in video).
In liver tissues from some subjects, the author found an association between the peak of viral RNA in a cluster and the number of cells in the cluster. This might suggest that infected hepatocytes depend on the robustness of viral replication in the hepatocyte most permissive to viral replication. Alternatively, the hepatocyte with the highest viral RNA copy number could have been the earliest infected cell of a cluster.
Cell-to-cell propagation of HCV could have important implications for vaccine design and drug development—strategies to inhibit entry of extracellular virions could be insufficient for HCV control if cell-to-cell spread of infection is rampant.
The authors hope for future studies with expanded viroscapes, so they can analyze expression of other host genes that control or support HCV replication.
Posted on December 16, 2013
by Kristine Novak, PhD, Science Editor
Using single-cell laser capture and high-resolution analysis, researchers show that hepatitis C virus (HCV) infects hepatocytes in the human liver in nonrandom clusters, whereas expression of anti-viral molecules is scattered among hepatocytes. The findings are presented in the December issue of Gastroenterology.
HCV predominantly infects hepatocytes, but most hepatocytes in the liver remain uninfected—HCV antigens have been observed to cluster. This suggests a localized mechanism of intra-hepatic propagation and control. Understanding this process could increase our understanding of infection and strategies for treatment.
Abraham J. Kandathil et al. analyzed liver samples from 4 patients with chronic HCV infection to estimate the proportion of infected hepatocytes and the amount of HCV RNA per cell using single-cell laser capture microdissection (LCM).
LCM unites light microscopy with a low-intensity ultraviolet laser, allowing researchers to ensnare enriched cellular material from tissue samples while preserving positional information, because the tissue is not homogenized. Kandathil et al. made improvements to the technique to increase its resolution, developing single-cell LCM, which allowed them to compare host and viral RNAs.
Studying viral replication in liver tissues from patients with chronic HCV infections, Kandathil et al. estimated the amount of HCV RNA per infected hepatocyte, to determine how the virus spreads in vivo and localize host cell expression of antiviral molecules.
The authors used their data to create a map of viral RNA in hepatocytes, which they called the viroscape. The viroscape shows hepatocytes containing narrow HCV replication peaks surrounded by broad regions with minimal or no HCV vRNA that resembled valleys (see video).
Kandathil et al. found that the proportion of HCV-infected hepatocytes per person ranged from 21% to 45%, and the level of viral RNA ranged from 1 to 50 IU/hepatocyte. However, infection was not random—the authors saw clusters of HCV-positive hepatocytes. These clusters in the hepatic viroscapes indicate cell-to-cell propagation of infection.
Kandathil et al. characterized the spatial association between intrahepatic HCV replication and innate immune signaling, and found that although expression of interferon-stimulated genes was sporadic, it was not specifically targeted toward or away from HCV-positive hepatocytes.
Clustering of HCV-infected hepatocytes did not appear to be caused by short-range immunologic control. IFITM3, an interferon-λ–induced protein that has direct antiviral effects against HCV in cell culture, did not appear to be directed specifically toward or away from infected hepatocytes (green in video).
In liver tissues from some subjects, the author found an association between the peak of viral RNA in a cluster and the number of cells in the cluster. This might suggest that infected hepatocytes depend on the robustness of viral replication in the hepatocyte most permissive to viral replication. Alternatively, the hepatocyte with the highest viral RNA copy number could have been the earliest infected cell of a cluster.
Cell-to-cell propagation of HCV could have important implications for vaccine design and drug development—strategies to inhibit entry of extracellular virions could be insufficient for HCV control if cell-to-cell spread of infection is rampant.
The authors hope for future studies with expanded viroscapes, so they can analyze expression of other host genes that control or support HCV replication.
Saturday, December 14, 2013
Treating HCV Aids Patients Who Also Have Diabetes
Published: Dec 14, 2013
This report is part of a 12-month Clinical Context series.
By Cole Petrochko, Staff Writer, MedPage Today
Patients with hepatitis C and diabetes had improved cardiovascular and renal outcomes when treated with pegylated interferon plus ribavirin, researchers found.
Compared with untreated and uninfected participants, patients with hepatitis C virus (HCV) and diabetes had significantly lower cumulative 8-year incidence of end-stage renal disease (1.1% for treated, infected patients versus 9.3% for untreated patients and 3.3% for uninfected patients, P<0.001) and stroke (3.1% versus 5.3% and 6.1%, respectively, P=0.01), according to Chun-Ying Wu, MD, PhD, of the Taichung Veterans General Hospital in Taiwan, and colleagues.
There was also a trend toward less acute coronary syndrome (4.1% versus 6.6% and 7.4%, respectively, P=0.05), they wrote online in the journal Hepatology. After adjustment, antiviral treatment remained significantly associated with improved outcomes for ischemic stroke and end-stage renal disease compared with those who were untreated.
The authors noted a "complex association" between diabetes, insulin resistance, and HCV infection. "On one hand, patients with HCV infection, as compared with the general population or those with another viral hepatitis, are more likely to develop insulin resistance and [diabetes]," they wrote.
"On the other hand, insulin resistance with or without overt manifestation of [diabetes] adversely impacts the clinical outcomes in HCV-infected patients, in terms of poor response to antiviral therapy, accelerated progression of liver fibrosis, and increased risk of hepatocellular carcinoma."
The mechanism by which HCV infection can lead to insulin resistance and diabetes is not known, but "appears to involve intracellular oxidative stress, dysregulation of cytokines, inhibition of insulin downstream signaling, and reduced expression of glucose transporters," they suggested.
Although treating HCV has been shown to lower insulin resistance and thus reduce the chance of developing diabetes, it is not clear how treating HCV infection in patients who already have diabetes will affect outcomes in this group.
To explore the issue further, the researchers studied 1,411 Taiwanese patients with diabetes and HCV infection who were treated with pegylated interferon plus ribavirin. These participants were matched one-to-one with HCV-infected but untreated control patients and one-to-four with diabetic patients who were not infected with HCV.
Primary outcomes included end-stage renal disease, acute coronary syndrome, and ischemic stroke. Associations were adjusted for hypertension, dyslipidemia, chronic obstructive pulmonary disease, and peripheral arterial occlusive disease.
Follow-up occurred over a mean 3.8, 3.7, and 3.8 years for the treated, untreated, and uninfected groups, respectively, with a maximum follow-up of 8 years.
Cumulative incidence of death at 8 years was highest among untreated patients (23.6%) versus the treated (13%) and uninfected (11.4%) participants.
Treatment was associated with a hazard ratio of 0.16 (95% CI 0.07-0.33) for end-stage renal disease, and of 0.53 (95% CI 0.30-0.93) for ischemic stroke. Treatment was not significantly associated with outcomes for acute coronary syndrome.
Risks for any of the three outcomes were lowest among treated patients in a multivariate-adjusted Cox proportional hazard model.
The investigators concluded that the anti-HCV therapy's effect on diabetes may be associated with its effects "in ameliorating insulin resistance and restoring glucose homeostasis, which has been convincingly demonstrated in previous studies," and that "antiviral therapy may also improve renal and cardiovascular outcomes through other mechanisms."
They noted that their outcomes could not be extrapolated to patients with significant comorbidity, that the data collected on HCV did not include viral genotype or viral load, there were no data on adherence to medication, and there was no measure of diabetic history and other physiological confounders. Their data also may not be generalizable to a non-Taiwanese population.
Primary source: Hepatology
Source reference: Wu CY, et al "Antiviral treatment for hepatitis C virus infection is associated with improved renal and cardiovascular outcomes in diabetic patients" Hepatology 2013; DOI: 10.1002/hep.26892.
The study was supported by Taiwan's National Health Research Insitute and Taiwan's National Science Council.
One co-author received support from Merck Sharp and Dohme, and Roche
http://www.medpagetoday.com/Gastroenterology/Hepatitis/43443
Thursday, December 12, 2013
Pursuit of All-Oral Hepatitis C Therapy: Where We're At, Where We're Going
Medscape Gastroenterology
HCV Treatment: Where We're At, Where We're Going
Rowen K. Zetterman, MD
December 11 2013
Hepatitis C Today
Worldwide, 170-200 million people, including 3.2-5 million Americans, are infected with hepatitis C virus (HCV). Clinical outcomes of chronic HCV infection include chronic hepatitis, cirrhosis, hepatocellular carcinoma (HCC), and complications of cirrhosis or HCC that result in the need for orthotopic liver transplantation. After liver transplantation, recurrence of HCV infection in the new graft is virtually uniform and can result once again in end-stage liver disease in need of transplantation.
There are 6 major genotypes of HCV, with genotype 1 accounting for 70%-75% of HCV infections in the United States. Genotype 1a is responsible for two thirds and genotype 1b for one third of genotype 1 infections. In treatment studies to date, genotype 1b is less likely to develop viral drug resistance and therefore has a higher treatment cure rate than HCV genotype 1a. Response to treatment is also influenced by the patient's interleukin 28B (IL28B) polymorphism, which results in a greater response in patients with the IL28B CC genotype than in those with IL28B TT genotype.[1]
Where We're At With Treatment
Interferon alpha has been used for 20 years to treat patients with HCV. The mechanism of viral efficacy for interferon has yet to be clearly established. Ribavirin was coupled to interferon therapy in 1998 and has resulted in a doubling of HCV treatment response.[2] Pegylated interferon alpha plus ribavirin has been used since 2001,[3] producing an overall 40% response for treated patients with HCV genotype 1.
Four classes of direct-acting antiviral (DAA) drugs have been developed, including NS3/4A protease inhibitors, NS5B nucleoside inhibitors, NS5B nonnucleoside inhibitors, and NS5A inhibitors.
In 2011, boceprevir and telaprevir, which are NS3/4A protease inhibitors, were approved for the treatment of patients infected with HCV genotype 1.[4,5] Pegylated interferon with ribavirin and either boceprevir or telaprevir is the current standard of care for HCV genotype 1, but this combination is less effective for genotypes 2 and 3. Boceprevir and telaprevir must be administered every 8 hours, and the rapid development of viral resistance prevents them from being used without pegylated interferon and ribavirin.[6,7] The combination of a protease inhibitor plus pegylated interferon and ribavirin results in more anemia and drug interactions than pegylated interferon and ribavirin alone.
The US Food and Drug Administration (FDA) recently approved the protease inhibitor simeprevir with pegylated interferon and ribavirin for the treatment of patients with HCV genotype 1. In addition, the FDA also approved sofosbuvir with pegylated interferon and ribavirin for the treatment of HCV genotype 1, and sofosbuvir and ribavirin for the treatment of HCV genotypes 2 and 3.
Boceprevir and Telaprevir
The current standard of care for HCV genotype 1 is either boceprevir or telaprevir with pegylated interferon and ribavirin. Therapy is 24-48 weeks in duration and results in a sustained viral response (SVR) in 67%-75% of patients. Patients with extended rapid viral response (eRVR) associated with a marked reduction in viral titer by 4 weeks of therapy and HCV absence at 12 weeks may require only 24 weeks of total treatment. Side effects, such as anemia, are frequent, as are drug interactions and medication intolerance.
Some have questioned whether the results of protease inhibitor therapy plus pegylated interferon and ribavirin are actually as good in general use as they were in early trials. A recent evaluation of Veterans Affairs treatment groups found that in similar patients who received either boceprevir or telaprevir, only 50% developed SVR.[8] With current therapy, treatment response is better in previously untreated patients, those with HCV genotype 1b, patients with IL28B CC genotype, and patients without advanced fibrosis or cirrhosis of the liver.
Where We're Going With Treatment
Simeprevir
Simeprevir, a new oral NS3/4A protease inhibitor, was recently approved by the FDA for the treatment of patients with HCV genotype 1 when administered with pegylated interferon and ribavirin.
Two studies (QUEST-1 and QUEST-2) evaluated oral simeprevir 150 mg/day for 12 weeks coupled with pegylated interferon and ribavirin, compared with pegylated interferon and ribavirin alone.[9] In the simeprevir group, 80% of patients had an eRVR at 12 weeks (compared with only 12% eRVR for pegylated interferon and ribavirin alone) and went on to receive 12 additional weeks of pegylated interferon and ribavirin. This resulted in a 91% SVR in the eRVR simeprevir group compared with 21% in other patients, including those treated as long as 48 weeks (QUEST-1). In the second trial (QUEST-2), simeprevir 150 mg/day for 12 weeks coupled with pegylated interferon and ribavirin for 24 weeks resulted in an SVR of 81%, compared with only 50% for interferon and ribavirin alone. No difference in response rates in patients with genotype 1a or 1b were found in this study.
In a third study (PROMISE) of patients in whom previous HCV treatment had failed, patients were treated with 12 weeks of simeprevir and 24 or 48 weeks of pegylated interferon and ribavirin. This study found that those with eRVR who had been treated for a total of 24 weeks had a 79% SVR, compared with 37% in those receiving placebo.[10] Patients with IL28B genotype CC had a 90% SVR, and those with advanced fibrosis had a 77% SVR, but SVR was only 45% in patients infected with HCV containing an NS3 Q80K mutation.
Sofosbuvir
Sofosbuvir, a nucleoside polymerase inhibitor, has been approved by the FDA for treatment of genotypes 1 through 6.
The open-label NEUTRINO trial[11] included patients with genotypes 1, 4, 5, or 6 who were treated with oral sofosbuvir (400 mg daily) and pegylated interferon with weight-based ribavirin for 12 weeks. This resulted in a 92% SVR for genotype 1a, 82% SVR for genotype 1b, 96% SVR for genotype 4, and 100% SVR for the few patients with genotype 5 or 6. Black patients had an SVR of 87%, compared with 91% in Hispanics and Latinos. The treatment response was better in patients with IL28B CC genotype and in those without cirrhosis.
The POSITRON and FUSION trials[12] evaluated sofosbuvir plus ribavirin in patients with genotype 2 and 3 HCV infections compared with placebo plus ribavirin. SVR was observed at 12 weeks of therapy in 78% of patients with previous treatment failure or patients who were previously unable to take pegylated interferon and ribavirin (POSITRON), and at 16 weeks in 73% of patients with previous treatment failure (FUSION). Both studies observed lower response in patients with genotype 3 and in those with cirrhosis.
Sofosbuvir with weight-based ribavirin oral therapy alone has been evaluated in small numbers of patients with HCV genotype 1. In a phase 2 trial of 25 previously untreated patients with all degrees of fibrosis, 68% achieved an SVR when treated with sofosbuvir 400 mg/day plus weight-based ribavirin compared with a 48% SVR in 25 patients treated with sofosbuvir 400 mg plus ribavirin 600 mg daily.[13] The study group included 83% black patients, 23% with advanced liver disease, 70% with HCV genotype 1a, and 48% with a body mass index > 30 kg/m2.
Drugs Under Development
Nearly 40 other drugs are currently under development and evaluation for the treatment of patients with HCV disease. These drugs include faldaprevir,[14,15] ledipasvir,[16] daclatasvir,[17] asunaprevir,[18] danoprevir,[19] alisporivir, and mericitabine, to name a few.
Pursuit of All-Oral Therapy
Will we ever have effective and completely oral therapies for HCV treatment?
For genotypes 2 and 3, that could happen by early 2014, with sofosbuvir plus ribavirin treatment being approved for HCV genotypes 2 and 3. Although patients with genotype 3 are less likely to achieve SVR than those with genotype 2, additional new drugs and studies of combinations of DAAs may further improve SVR for both genotypes.
The meeting of the American Association for the Study of Liver Diseases (AASLD) in November 2013 included several presentations about oral therapy for HCV treatment. A fixed combination of oral sofosbuvir 400 mg and the NS5A inhibitor ledipasvir 60 mg with ribavirin for 12 weeks achieved a 100% SVR in previously treated patients with HCV genotype 1 infection and advanced fibrosis of the liver.[24] Oral sofosbuvir plus ribavirin in patients with HCV and HIV infection (CD4 count > 500 cells/µL) resulted in an SVR of 76% in patients with genotype 1, 88% in those with genotype 2, and 67% in those with genotype 3.[25] A combination of sofosbuvir and simeprevir plus ribavirin for 12 weeks (COSMOS trial) resulted in a 96% SVR in previously treated patients with genotype 1 and a 93% SVR when sofosbuvir and simeprevir were given alone.[26]
These studies suggest that new DAAs and future combinations of DAAs will identify new treatments for FDA approval that will lead to all oral therapies for HCV infection.
Cost Considerations
http://www.medscape.com/viewarticle/817546_1
HCV Treatment: Where We're At, Where We're Going
Rowen K. Zetterman, MD
December 11 2013
Hepatitis C Today
Worldwide, 170-200 million people, including 3.2-5 million Americans, are infected with hepatitis C virus (HCV). Clinical outcomes of chronic HCV infection include chronic hepatitis, cirrhosis, hepatocellular carcinoma (HCC), and complications of cirrhosis or HCC that result in the need for orthotopic liver transplantation. After liver transplantation, recurrence of HCV infection in the new graft is virtually uniform and can result once again in end-stage liver disease in need of transplantation.
There are 6 major genotypes of HCV, with genotype 1 accounting for 70%-75% of HCV infections in the United States. Genotype 1a is responsible for two thirds and genotype 1b for one third of genotype 1 infections. In treatment studies to date, genotype 1b is less likely to develop viral drug resistance and therefore has a higher treatment cure rate than HCV genotype 1a. Response to treatment is also influenced by the patient's interleukin 28B (IL28B) polymorphism, which results in a greater response in patients with the IL28B CC genotype than in those with IL28B TT genotype.[1]
Where We're At With Treatment
Interferon alpha has been used for 20 years to treat patients with HCV. The mechanism of viral efficacy for interferon has yet to be clearly established. Ribavirin was coupled to interferon therapy in 1998 and has resulted in a doubling of HCV treatment response.[2] Pegylated interferon alpha plus ribavirin has been used since 2001,[3] producing an overall 40% response for treated patients with HCV genotype 1.
Four classes of direct-acting antiviral (DAA) drugs have been developed, including NS3/4A protease inhibitors, NS5B nucleoside inhibitors, NS5B nonnucleoside inhibitors, and NS5A inhibitors.
In 2011, boceprevir and telaprevir, which are NS3/4A protease inhibitors, were approved for the treatment of patients infected with HCV genotype 1.[4,5] Pegylated interferon with ribavirin and either boceprevir or telaprevir is the current standard of care for HCV genotype 1, but this combination is less effective for genotypes 2 and 3. Boceprevir and telaprevir must be administered every 8 hours, and the rapid development of viral resistance prevents them from being used without pegylated interferon and ribavirin.[6,7] The combination of a protease inhibitor plus pegylated interferon and ribavirin results in more anemia and drug interactions than pegylated interferon and ribavirin alone.
The US Food and Drug Administration (FDA) recently approved the protease inhibitor simeprevir with pegylated interferon and ribavirin for the treatment of patients with HCV genotype 1. In addition, the FDA also approved sofosbuvir with pegylated interferon and ribavirin for the treatment of HCV genotype 1, and sofosbuvir and ribavirin for the treatment of HCV genotypes 2 and 3.
Boceprevir and Telaprevir
The current standard of care for HCV genotype 1 is either boceprevir or telaprevir with pegylated interferon and ribavirin. Therapy is 24-48 weeks in duration and results in a sustained viral response (SVR) in 67%-75% of patients. Patients with extended rapid viral response (eRVR) associated with a marked reduction in viral titer by 4 weeks of therapy and HCV absence at 12 weeks may require only 24 weeks of total treatment. Side effects, such as anemia, are frequent, as are drug interactions and medication intolerance.
Some have questioned whether the results of protease inhibitor therapy plus pegylated interferon and ribavirin are actually as good in general use as they were in early trials. A recent evaluation of Veterans Affairs treatment groups found that in similar patients who received either boceprevir or telaprevir, only 50% developed SVR.[8] With current therapy, treatment response is better in previously untreated patients, those with HCV genotype 1b, patients with IL28B CC genotype, and patients without advanced fibrosis or cirrhosis of the liver.
Where We're Going With Treatment
Simeprevir
Simeprevir, a new oral NS3/4A protease inhibitor, was recently approved by the FDA for the treatment of patients with HCV genotype 1 when administered with pegylated interferon and ribavirin.
Two studies (QUEST-1 and QUEST-2) evaluated oral simeprevir 150 mg/day for 12 weeks coupled with pegylated interferon and ribavirin, compared with pegylated interferon and ribavirin alone.[9] In the simeprevir group, 80% of patients had an eRVR at 12 weeks (compared with only 12% eRVR for pegylated interferon and ribavirin alone) and went on to receive 12 additional weeks of pegylated interferon and ribavirin. This resulted in a 91% SVR in the eRVR simeprevir group compared with 21% in other patients, including those treated as long as 48 weeks (QUEST-1). In the second trial (QUEST-2), simeprevir 150 mg/day for 12 weeks coupled with pegylated interferon and ribavirin for 24 weeks resulted in an SVR of 81%, compared with only 50% for interferon and ribavirin alone. No difference in response rates in patients with genotype 1a or 1b were found in this study.
In a third study (PROMISE) of patients in whom previous HCV treatment had failed, patients were treated with 12 weeks of simeprevir and 24 or 48 weeks of pegylated interferon and ribavirin. This study found that those with eRVR who had been treated for a total of 24 weeks had a 79% SVR, compared with 37% in those receiving placebo.[10] Patients with IL28B genotype CC had a 90% SVR, and those with advanced fibrosis had a 77% SVR, but SVR was only 45% in patients infected with HCV containing an NS3 Q80K mutation.
Sofosbuvir
Sofosbuvir, a nucleoside polymerase inhibitor, has been approved by the FDA for treatment of genotypes 1 through 6.
The open-label NEUTRINO trial[11] included patients with genotypes 1, 4, 5, or 6 who were treated with oral sofosbuvir (400 mg daily) and pegylated interferon with weight-based ribavirin for 12 weeks. This resulted in a 92% SVR for genotype 1a, 82% SVR for genotype 1b, 96% SVR for genotype 4, and 100% SVR for the few patients with genotype 5 or 6. Black patients had an SVR of 87%, compared with 91% in Hispanics and Latinos. The treatment response was better in patients with IL28B CC genotype and in those without cirrhosis.
The POSITRON and FUSION trials[12] evaluated sofosbuvir plus ribavirin in patients with genotype 2 and 3 HCV infections compared with placebo plus ribavirin. SVR was observed at 12 weeks of therapy in 78% of patients with previous treatment failure or patients who were previously unable to take pegylated interferon and ribavirin (POSITRON), and at 16 weeks in 73% of patients with previous treatment failure (FUSION). Both studies observed lower response in patients with genotype 3 and in those with cirrhosis.
Sofosbuvir with weight-based ribavirin oral therapy alone has been evaluated in small numbers of patients with HCV genotype 1. In a phase 2 trial of 25 previously untreated patients with all degrees of fibrosis, 68% achieved an SVR when treated with sofosbuvir 400 mg/day plus weight-based ribavirin compared with a 48% SVR in 25 patients treated with sofosbuvir 400 mg plus ribavirin 600 mg daily.[13] The study group included 83% black patients, 23% with advanced liver disease, 70% with HCV genotype 1a, and 48% with a body mass index > 30 kg/m2.
Drugs Under Development
Nearly 40 other drugs are currently under development and evaluation for the treatment of patients with HCV disease. These drugs include faldaprevir,[14,15] ledipasvir,[16] daclatasvir,[17] asunaprevir,[18] danoprevir,[19] alisporivir, and mericitabine, to name a few.
Pursuit of All-Oral Therapy
Will we ever have effective and completely oral therapies for HCV treatment?
For genotypes 2 and 3, that could happen by early 2014, with sofosbuvir plus ribavirin treatment being approved for HCV genotypes 2 and 3. Although patients with genotype 3 are less likely to achieve SVR than those with genotype 2, additional new drugs and studies of combinations of DAAs may further improve SVR for both genotypes.
The meeting of the American Association for the Study of Liver Diseases (AASLD) in November 2013 included several presentations about oral therapy for HCV treatment. A fixed combination of oral sofosbuvir 400 mg and the NS5A inhibitor ledipasvir 60 mg with ribavirin for 12 weeks achieved a 100% SVR in previously treated patients with HCV genotype 1 infection and advanced fibrosis of the liver.[24] Oral sofosbuvir plus ribavirin in patients with HCV and HIV infection (CD4 count > 500 cells/µL) resulted in an SVR of 76% in patients with genotype 1, 88% in those with genotype 2, and 67% in those with genotype 3.[25] A combination of sofosbuvir and simeprevir plus ribavirin for 12 weeks (COSMOS trial) resulted in a 96% SVR in previously treated patients with genotype 1 and a 93% SVR when sofosbuvir and simeprevir were given alone.[26]
These studies suggest that new DAAs and future combinations of DAAs will identify new treatments for FDA approval that will lead to all oral therapies for HCV infection.
Cost Considerations
What of the cost of new DAAs?
Although the pricing of simeprevir or sofosbuvir has not been established, some have suggested that approximately $80,000 per treated patient will be the likely cost for each of these new drugs. How does that compare with the cost of current standard-of-care treatment with pegylated interferon, ribavirin, and boceprevir or telaprevir?
A presentation at the AASLD meeting suggested that the cost of the current standard of care is $189,000 per SVR achieved.[27] In a study of 147 patients, of whom 44% achieved SVR, the direct per-patient costs of telaprevir ($55,273), pegylated interferon ($30,418), and ribavirin ($4926) were supplemented by the additional costs for erythropoietin, transfusions, granulocyte colony-stimulating factor, emergency department visits, and hospitalizations, resulting in a median cost of $83,509 per treated patient. Because SVR was achieved in only 44% of those who were treated, the cost of treatment per successful SVR ($83,509 per treated patient × 2.27, because only 44% of treated patients achieved SVR) was approximately $189,000.
A Future of Improved Treatments
The large number of clinical trials of new DAA drugs to treat HCV infection is encouraging. Simeprevir and sofosbuvir should be available sometime in early 2014, to be coupled with pegylated interferon and ribavirin for the treatment of genotype 1, and sofosbuvir plus ribavirin (but without interferon) for genotypes 2 and 3.
The reduced pill burden, shortened treatment time even with pegylated interferon and ribavirin, similar or improved response rates compared with current protease inhibitor/pegylated interferon and ribavirin therapy, apparent reduction of drug interactions with these newer agents, and somewhat diminished effect of genetic response factors (such as IL28B) all suggest a future of improved treatments for the HCV-infected patient. It seems reasonable that many HCV-infected patients can wait for new drugs to become available.
Although the pricing of simeprevir or sofosbuvir has not been established, some have suggested that approximately $80,000 per treated patient will be the likely cost for each of these new drugs. How does that compare with the cost of current standard-of-care treatment with pegylated interferon, ribavirin, and boceprevir or telaprevir?
A presentation at the AASLD meeting suggested that the cost of the current standard of care is $189,000 per SVR achieved.[27] In a study of 147 patients, of whom 44% achieved SVR, the direct per-patient costs of telaprevir ($55,273), pegylated interferon ($30,418), and ribavirin ($4926) were supplemented by the additional costs for erythropoietin, transfusions, granulocyte colony-stimulating factor, emergency department visits, and hospitalizations, resulting in a median cost of $83,509 per treated patient. Because SVR was achieved in only 44% of those who were treated, the cost of treatment per successful SVR ($83,509 per treated patient × 2.27, because only 44% of treated patients achieved SVR) was approximately $189,000.
A Future of Improved Treatments
The large number of clinical trials of new DAA drugs to treat HCV infection is encouraging. Simeprevir and sofosbuvir should be available sometime in early 2014, to be coupled with pegylated interferon and ribavirin for the treatment of genotype 1, and sofosbuvir plus ribavirin (but without interferon) for genotypes 2 and 3.
The reduced pill burden, shortened treatment time even with pegylated interferon and ribavirin, similar or improved response rates compared with current protease inhibitor/pegylated interferon and ribavirin therapy, apparent reduction of drug interactions with these newer agents, and somewhat diminished effect of genetic response factors (such as IL28B) all suggest a future of improved treatments for the HCV-infected patient. It seems reasonable that many HCV-infected patients can wait for new drugs to become available.
http://www.medscape.com/viewarticle/817546_1
Gut Reaction: Black Kids Don't Fare as Well With Liver Transplants
Gut Reaction: Black Kids Don't Fare as Well With Liver Transplants
Published: Dec 11, 2013
Primary source: Liver Transplantation
Source reference: Patzer RE, et al "Racial and socioeconomic disparities in pediatric and young adult liver transplant outcomes" Liver Transpl 2013; DOI: 10.1002/lt.23769.
http://www.medpagetoday.com/Gastroenterology/LiverTransplantation/43373
Published: Dec 11, 2013
By Cole Petrochko, Staff Writer, MedPage Today
Primary source: Liver Transplantation
Source reference: Patzer RE, et al "Racial and socioeconomic disparities in pediatric and young adult liver transplant outcomes" Liver Transpl 2013; DOI: 10.1002/lt.23769.
http://www.medpagetoday.com/Gastroenterology/LiverTransplantation/43373
Antivirals for HCV improve kidney and cardiovascular diseases in diabetic patients
Antivirals for HCV improve kidney and cardiovascular diseases in diabetic patients
Researchers from Taiwan reveal that antiviral therapy for hepatitis C virus (HCV) improves kidney and cardiovascular outcomes for patients with diabetes. Results of the study published in Hepatology, a journal of the American Association for the Study of Liver Diseases, show that incidences of kidney disease, stroke, and heart attack were lower in patients treated with pegylated interferon and ribavirin compared to HCV patients not treated with antivirals or diabetic patients not infected with the virus.
The World Health Organization (WHO) estimates that diabetes affects 347 million individuals worldwide and another 170 million people are living with chronic HCV. Previous research suggests a link between diabetes and chronic HCV, with HCV infected individuals having a greater chance of developing insulin resistance and diabetes. Moreover, HCV patients with insulin resistance, with or without diabetes, have a poor response to antiviral treatment, increased progression of liver fibrosis and greater risk of developing liver cancer (hepatocellular carcinoma).
"There is growing evidence of an association between diabetes and HCV," explains lead author, Chun-Ying Wu, MD, PhD, MPH from Taichung Veterans General Hospital in Taiwan. "Our study investigates if antiviral therapy used to treat HCV infection also improves diabetes outcomes."
For this population-based study researchers used data from the Taiwan National Health Insurance Research Database, which has collected healthcare details for all residents of the country since 1997. The team indentified 1, 411 patients with diabetes and HCV who were enrolled in the study, and received pegylated interferon plus ribavirin. There were also 1,411 individuals in the untreated group and 5,644 patients with diabetes and without HCV in the uninfected cohort. Follow-up for all participants was from 2003 to 2011.
Findings indicate that the 8-year cumulative incidences of end-stage renal disease in the treated, untreated and uninfected groups were 1.1%, 9.3%, and 3.3%, respectively. Further analysis found stroke incidence was 3.1% for treated patients, 5.3% for untreated and 6.1 for uninfected subjects. Acute coronary syndrome—an umbrella term the American Heart Association uses to define diseases, such as heart attack or angina, where blood to the heart is blocked—occurred in 4.1%, 6.6% and 7.4% of treated, untreated and uninfected patients.
"Our findings suggest that HCV may cause clinical complications related to diabetes. But these issues are mitigated by HCV antiviral therapy, specifically pegylated interferon plus ribavirin, which was found to reduce risks of kidney disease, stroke and cardiovascular diseases in diabetic patients," concludes Dr. Wu. The authors recommend further examination of the underlying relationship between HCV and diabetes.
EASL publishes revised clinical practice guidelines to optimise the management of hepatitis C virus
More information: "Antiviral Treatment for Hepatitis C Virus Infection is Associated with Improved Renal and Cardiovascular Outcomes in Diabetic Patients." Yao-Chun Hsu, Jaw-Town Lin, Hsiu J. Ho, Yu-Hsi Kao, Yen-Tsung Huang, Nai-Wan Hsiao, Ming-Shiang Wu, Yi-Ya Liu and Chun-Ying Wu. Hepatology; DOI: 10.1002/hep.26892
Researchers from Taiwan reveal that antiviral therapy for hepatitis C virus (HCV) improves kidney and cardiovascular outcomes for patients with diabetes. Results of the study published in Hepatology, a journal of the American Association for the Study of Liver Diseases, show that incidences of kidney disease, stroke, and heart attack were lower in patients treated with pegylated interferon and ribavirin compared to HCV patients not treated with antivirals or diabetic patients not infected with the virus.
The World Health Organization (WHO) estimates that diabetes affects 347 million individuals worldwide and another 170 million people are living with chronic HCV. Previous research suggests a link between diabetes and chronic HCV, with HCV infected individuals having a greater chance of developing insulin resistance and diabetes. Moreover, HCV patients with insulin resistance, with or without diabetes, have a poor response to antiviral treatment, increased progression of liver fibrosis and greater risk of developing liver cancer (hepatocellular carcinoma).
"There is growing evidence of an association between diabetes and HCV," explains lead author, Chun-Ying Wu, MD, PhD, MPH from Taichung Veterans General Hospital in Taiwan. "Our study investigates if antiviral therapy used to treat HCV infection also improves diabetes outcomes."
For this population-based study researchers used data from the Taiwan National Health Insurance Research Database, which has collected healthcare details for all residents of the country since 1997. The team indentified 1, 411 patients with diabetes and HCV who were enrolled in the study, and received pegylated interferon plus ribavirin. There were also 1,411 individuals in the untreated group and 5,644 patients with diabetes and without HCV in the uninfected cohort. Follow-up for all participants was from 2003 to 2011.
Findings indicate that the 8-year cumulative incidences of end-stage renal disease in the treated, untreated and uninfected groups were 1.1%, 9.3%, and 3.3%, respectively. Further analysis found stroke incidence was 3.1% for treated patients, 5.3% for untreated and 6.1 for uninfected subjects. Acute coronary syndrome—an umbrella term the American Heart Association uses to define diseases, such as heart attack or angina, where blood to the heart is blocked—occurred in 4.1%, 6.6% and 7.4% of treated, untreated and uninfected patients.
"Our findings suggest that HCV may cause clinical complications related to diabetes. But these issues are mitigated by HCV antiviral therapy, specifically pegylated interferon plus ribavirin, which was found to reduce risks of kidney disease, stroke and cardiovascular diseases in diabetic patients," concludes Dr. Wu. The authors recommend further examination of the underlying relationship between HCV and diabetes.
EASL publishes revised clinical practice guidelines to optimise the management of hepatitis C virus
More information: "Antiviral Treatment for Hepatitis C Virus Infection is Associated with Improved Renal and Cardiovascular Outcomes in Diabetic Patients." Yao-Chun Hsu, Jaw-Town Lin, Hsiu J. Ho, Yu-Hsi Kao, Yen-Tsung Huang, Nai-Wan Hsiao, Ming-Shiang Wu, Yi-Ya Liu and Chun-Ying Wu. Hepatology; DOI: 10.1002/hep.26892
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