University of Maryland School of Pharmacy researchers have developed a mathematical model for choosing an appropriate dosage of the hepatitis medications for individual patients. The work helps explain why African American patients tend to not respond as well to the drugs as other patients.
For the work, student researcher Runyan Jin, MD, PhD, won the best student research award and a $1,000 prize for her work at the 2010 American College of Clinical Pharmacology (ACCP) scientific meeting. Her project involved analyzing 900 blood samples from 400 patients enrolled in a multi-center trial to determine why hepatitis therapy works for some patients, but not others.
Hepatitis C is a serious liver disease caused by the hepatitis C virus and if not treated can lead to liver cancer and death. African Americans have a higher incidence and death from liver cancer.
The therapy, consisting of the anti-virus drug ribavirin, along with injections of the protective protein interferon, cures hepatitis C in some patients within six months due to a sustained viral response [SVR], suppressing the virus to undetectable levels for an extended period of time.
"Our question was why some patients in the large trial did not get this SVR cure. The response rate of African American patients was about half that of non-African Americans," says Thomas Dowling PharmD, PhD, associate professor in the School of Pharmacy's Clinical Pharmacology Unit. [Jin and Dowling are pictured above.]
Jin, who is Dowling's post-doctorate student and is already a pediatrician, reported that blood from the African American patients contained lower levels of the ribavirin drug than blood from non-African American patients on the same therapy. Especially in early stages of the therapy, the ribavirin was not getting into the blood system as efficiently in African Americans as in Caucasians. The mathematical model showed that the African Americans had a pharmacodynamic difference somehow in the distributional volume, which means the space where the drug moves, says Dowling.
The different response by African Americans to ribavirin is not the first time medical science has seen such a drug response difference between races.
"We are trying to model how to change the dosage not just change dose recommendations now. ýEventually personalized therapy will mean proper doses for each patient's genotype."
Pediatrician Jin hopes that her pharmacy work on anti-virus mediations and how they work in different people, pharmacodynamics, will also be useful in treating children. "This is especially important in children to get the correct dosages for safe and effective treatments." ý
"I was very lucky," says Jin. "When I was a second year [PhD]) student, I was looking for a research project in pharmacodynamics." She applied a mathematical method called Bayesian statistics to simplify the pharmacodynamic relationship between the drug and the 400 patients in the 2006 study, a method taught to her by Michael Fossler, PharmD, PhD, an alum of the School of Pharmacy now with drug maker GlaxoSmithKline.
"Runyan pulled a very nice story together with direct clinical applications. What we are faced with now [in drug development] is studies that are now so very expensive, says Fossler. "Bayesian methodology helps us cut our losses saves some patients from taking drugs that don't work sometimes."
Jin's research poster, "Population Pharmacodynamic Model in Patients with Chronic Hepatitis C Virus Genotype 1," won the 2010 Wayne A. Colburn Memorial Award at the annual ACCP. She has accepted a position at the U.S. Food and Drug Administration. ýIn her new career, she says, "I want to be an expert in this area of quantitative clinical pharmacology."
Posting Date: 12/06/2010
Contact Name: Steve Berberich
Contact Phone: 410-706-0023
Contact Email: sberb001@umaryland.edu
Source
December 6, 2010
New HCV Drugs at AASLD
From NATAP:
from Jules: below are links to key data reports on the many new oral HCV drugs at various stages of development and there are numerous drugs in development from the various new classes which include protease inhibitors, polymerase inhibitors (nucleosides, nucletides, various types of NNRTIs), NS5A inhibitors, and if pegIFN must be used there is peg-lambda IFN. Of course Vertex & Merck presented phase 3 data results at AASLD but also there were many data updates from the other drugs in earlier stages of development. Response-Gulded Therapy (RGT) will be the new mantra in HCV therapy once the 1st oral drugs hit the market and this means patients & clinicians must bring in patients at time-checks early after starting therapy to see if viral load is undetectable or not; these time-point checks to decide if a patient should continue or stop therapy, and I see this concept continuing to be refined over time, we will move towards 16 week or even 12 week total therapy as we improve regimens to include 3 or 4 orals with or without peg/rbv.
In the Vertex large phase 3 ADVANCE Study of the HCV protease inhibitor telaprevir, which included over 1000 genotype 1 treatment-naïve patients presented at AASLD, study patients who received telaprevir plus Pegasys/rbv had a significantly higher SVR (Sustained Viral Response, cure): 75% vs 44% of patients who received just Pegasys/rbv. These numbers included patients who had either 24 or 48 weeks total therapy. Patients, both blacks and whites, who had undetectable viral load at the early time-checkpoints, weeks 4 and 12, about 90% achieved SVR. In the Merck SPRINT-2 phase 3 Study of boceprevir presented at AASLD, over 1000 genotype 1 treatment-naïve patients participated, patients received either boceprevir plus Pegintron/rbv or just Pegintron/rbv, with 67-71% of non-Blacks achieving a SVR (cure) vs 40% for study patients who received Pegintron/rbv, and 42-53% of Blacks achieving cure vs 23% who received only Pegintron/rbv, these results were for patients who had a total duration of therapy of 24 or 48 weeks. An undetectable viral load at the early time-check-points in this study, weeks 8 and 24, also achieved high rates of SVR, cure.
How much affect on outcome (SVR) will IL28B and the genotype 1a vs 1b have once oral therapy are added to peg/RBV remains to be seen, but certainly as you add more than 1 oral to peg/rbv their impact will diminish & eventually be minimal or disappear altogether. BMS presented the early data, the 1st data in null-responders receiving 2 orals only or 2 orals plus peg/rbv, the results from this study were highly anticipated and begin to give us important information on treatment without peg/rbv but also in treating null-responders, as all 10 null-responders had undetectable viral load after 12 weeks with all 4 drugs. After initial monotherapy ABT-450 looked very potent, perhaps a 6-log drug. The nucleoside polymerase R7128 shows good 12 week data underscoring the importance that this drug or class appears not be associated with resistance developing easily & early, and this is important. Pharmasset presented data on 2 nucleotides with potency & also the possibility of not be associated with resistance developing. The BMS NS5A is potent. Some drugs are administered once daily, some three times daily, the side effects profiles differ between the drugs, and success with therapy will require management of side effects, like anemia. The data from both Vertex & Merck show that African-Americans can have response rates as high as whites if they have early RGT results, that is if the viral load is undetectable at the early-time-points the cure or SVR rates are equally high for blacks, latinos and whites.
Continue Reading ...
from Jules: below are links to key data reports on the many new oral HCV drugs at various stages of development and there are numerous drugs in development from the various new classes which include protease inhibitors, polymerase inhibitors (nucleosides, nucletides, various types of NNRTIs), NS5A inhibitors, and if pegIFN must be used there is peg-lambda IFN. Of course Vertex & Merck presented phase 3 data results at AASLD but also there were many data updates from the other drugs in earlier stages of development. Response-Gulded Therapy (RGT) will be the new mantra in HCV therapy once the 1st oral drugs hit the market and this means patients & clinicians must bring in patients at time-checks early after starting therapy to see if viral load is undetectable or not; these time-point checks to decide if a patient should continue or stop therapy, and I see this concept continuing to be refined over time, we will move towards 16 week or even 12 week total therapy as we improve regimens to include 3 or 4 orals with or without peg/rbv.
In the Vertex large phase 3 ADVANCE Study of the HCV protease inhibitor telaprevir, which included over 1000 genotype 1 treatment-naïve patients presented at AASLD, study patients who received telaprevir plus Pegasys/rbv had a significantly higher SVR (Sustained Viral Response, cure): 75% vs 44% of patients who received just Pegasys/rbv. These numbers included patients who had either 24 or 48 weeks total therapy. Patients, both blacks and whites, who had undetectable viral load at the early time-checkpoints, weeks 4 and 12, about 90% achieved SVR. In the Merck SPRINT-2 phase 3 Study of boceprevir presented at AASLD, over 1000 genotype 1 treatment-naïve patients participated, patients received either boceprevir plus Pegintron/rbv or just Pegintron/rbv, with 67-71% of non-Blacks achieving a SVR (cure) vs 40% for study patients who received Pegintron/rbv, and 42-53% of Blacks achieving cure vs 23% who received only Pegintron/rbv, these results were for patients who had a total duration of therapy of 24 or 48 weeks. An undetectable viral load at the early time-check-points in this study, weeks 8 and 24, also achieved high rates of SVR, cure.
How much affect on outcome (SVR) will IL28B and the genotype 1a vs 1b have once oral therapy are added to peg/RBV remains to be seen, but certainly as you add more than 1 oral to peg/rbv their impact will diminish & eventually be minimal or disappear altogether. BMS presented the early data, the 1st data in null-responders receiving 2 orals only or 2 orals plus peg/rbv, the results from this study were highly anticipated and begin to give us important information on treatment without peg/rbv but also in treating null-responders, as all 10 null-responders had undetectable viral load after 12 weeks with all 4 drugs. After initial monotherapy ABT-450 looked very potent, perhaps a 6-log drug. The nucleoside polymerase R7128 shows good 12 week data underscoring the importance that this drug or class appears not be associated with resistance developing easily & early, and this is important. Pharmasset presented data on 2 nucleotides with potency & also the possibility of not be associated with resistance developing. The BMS NS5A is potent. Some drugs are administered once daily, some three times daily, the side effects profiles differ between the drugs, and success with therapy will require management of side effects, like anemia. The data from both Vertex & Merck show that African-Americans can have response rates as high as whites if they have early RGT results, that is if the viral load is undetectable at the early-time-points the cure or SVR rates are equally high for blacks, latinos and whites.
Continue Reading ...
Irreversible inhibition of a protease central to hepatitis C infection; New HCV Protease AVL-192: Study
Download the PDF here
Mon, Nov 29, 2010
A new study has demonstrated that irreversible covalent inhibition can increase selectivity, potency and duration of action, broadens applications for targeted covalent drugs to the protease gene family.
Avila Therapeutics Inc., a biotechnology company developing novel targeted covalent drugs, has demonstrated the first-ever selective irreversible inhibition of a viral protease using a targeted covalent drug.
Avila has used its proprietary Avilomics platform to design covalent irreversible protease inhibitors that are highly selective, potent and with superior duration of action as compared to conventional protease inhibitors.
The research has demonstrated that covalent drugs can be designed and targeted to irreversibly and covalently bond to molecular domains specific to proteases.
"This research elevates covalent drug design to a fundamentally new level. By creating extremely selective protease inhibitors with their platform, Avila is showing the remarkable therapeutic potential of irreversible covalent drugs to address a broad spectrum of drug targets," said Simon Campbell , a renowned scientist.
"This approach can make a difference to patients living with HCV infection, and we expect to make an impact in other important areas such as cancer and inflammatory disease," said said Juswinder Singh, co-author of the paper.
In order to maximize selectivity and minimize off-target effects, the irreversible covalent inhibitors of HCV protease were designed to covalently target a unique structure in the HCV protease not found in human proteases. Key findings include:
A representative irreversible covalent inhibitor designed, by Avila, was shown to inhibit the HCV protease (also known as "NS3") in cells at a concentration of 6 nM.
Specific covalent bond formation between the drug and target protease was demonstrated through use of mass spectrometry and also x-ray crystallography.
The findings were published in the journal Nature Chemical Biology. (ANI)
-------------------------------------------
Avila Presents New Data on its Novel, Orally-Available Targeted Covalent Drug, AVL-192
Covalent Inhibition Achieves Superior Potency Against Drug-Resistant HCV Mutants
BOSTON and WALTHAM, MA - November 2, 2010 - Avila TherapeuticsTM, Inc., a biotechnology company developing novel targeted covalent drugs, presented results today of preclinical studies that demonstrate its orally-available targeted covalent drug candidate, AVL-192, achieves superior potency against drug-resistant mutations of the Hepatitis C Virus (HCV). These new data were presented today at the Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) international meeting in Boston, Massachusetts.
HCV protease (also known as NS3) is a promising target of intervention for the treatment of hepatitis C infection. However, medicines currently in late stages of clinical development are vulnerable to drug- resistant mutations. AVL-192 is a novel, orally available compound that can rapidly and completely silence the HCV protease through highly selective, irreversible covalent bonding to the target protein. Preclinical data have demonstrated that AVL-192 achieves very high potency and selectivity for NS3 and also potently and effectively inhibits the drug-resistant mutations observed clinically.
Avila's covalent approach to silencing the NS3 protein has resulted in a product candidate with a potential best-in-class profile due to the ability to retain potency against clinically-arising resistance mutations, and potential breadth of activity across HCV genotypes with anticipated once-per-day dosing.
In a poster presentation at the meeting, entitled, "Second Generation of Covalent Irreversible Inhibitors Have Superior Potency Across Genotypes and Drug Resistant Mutants," data were presented from preclinical studies that evaluated the efficacy of AVL-192 in biochemical and cell culture studies. Highlights of the data demonstrate:
· AVL-192 has a time-dependent mode of action that delivers potent and rapid inhibition of WT NS3/4A and retains high potency against drug-resistant mutant NS3/4A proteases;
· AVL-192 is able to inhibit the protease long after the compound is removed, offering the benefit of less frequent dosing;
· AVL-192 as monotherapy can be curative in the replicon clearance assay;
· AVL-192 is highly selective and spares host proteases; and
· AVL-192 has high plasma exposure following oral administration in rats and dogs.
"These new data reinforce our belief that our targeted covalent drug candidate AVL-192 has the potential to be a best-in-class, pan-genotype HCV therapeutic due to its unique mechanism of action," said Juswinder Singh, Ph.D., Avila's Founder and Chief Scientific Officer.
About Avila TherapeuticsTM, Inc.
Avila focuses on design and development of targeted covalent drugs to achieve best-in-class outcomes that cannot be achieved through traditional chemistries. This approach is called "protein silencing". The company's product pipeline has been built using its proprietary AvilomicsTM platform and is currently focused on viral infection, cancer and autoimmune disease. Avila is funded by leading venture capital firms: Abingworth, Advent Venture Partners, Atlas Venture, Novartis Option Fund, and Polaris Venture Partners. For additional information, please visit http://www.avilatx.com/
------------------------------------
Selective irreversible inhibition of a protease by targeting a noncatalytic cysteine
Brief Communication
Nature Chemical Biology, 28 November 2010
Margit Hagel, Deqiang Niu, Thia St Martin, Michael P Sheets, Lixin Qiao, Hugues Bernard, Russell M Karp, Zhendong Zhu, Matthew T Labenski, Prasoon Chaturvedi, Mariana Nacht, William F Westlin, Russell C Petter & Juswinder Singh 1Avila Therapeutics, Inc., Waltham, Massachusetts, USA. 2Millenium: The Takeda Oncology Company, Cambridge, Massachusetts, USA. *e-mail: jsingh@avilatx.com
Designing selective inhibitors of proteases has proven problematic, in part because pharmacophores that confer potency exploit the conserved catalytic apparatus. We developed a fundamentally different approach by designing irreversible inhibitors that target noncatalytic cysteines that are structurally unique to a target in a protein family. We have successfully applied this approach to the important therapeutic target HCV protease, which has broad implications for the design of other selective protease inhibitors.
The fundamental challenge in designing protease inhibitors is to achieve potency without sacrificing selectivity. This problem arises frequently because the typical protease inhibitor achieves potency through covalent interactions with the catalytic apparatus, yet such pharmacophores also confer affinity for other proteases in the same mechanistic family1. This is a significant challenge for protease drug design, because over 500 proteases exist in the human genome. Achieving selectivity while targeting the catalytic machinery is thus particularly difficult2.
Covalent irreversible drugs that form persistent, nonlabile covalent bonds yield unique therapeutic benefits including rapid onset of inhibition, greater potency, longer duration of drug action and potent and persistent activity against mutations that would otherwise lead to drug resistance3. There are many examples of drugs that work through irreversible covalent bonding that have proven to be safe and successful therapies for a wide variety of indications4. Despite their prevalence, to date covalent drugs have largely been discovered serendipitously, and general methods to facilitate their deliberate discovery and design have yet to be described.
HCV NS3/4A viral protease (HCVP) activity is essential for viral replication5 and has been recently validated as a clinical target6, 7, 8, 9, 10, 11, 12, 13, 14, 15. Protease inhibitors such as telaprevir exemplify the challenges of covalent targeting of the catalytic binding site; upon binding to HCVP, the α-ketoamide forms a reversible covalent linkage with the catalytic serine that is conserved within proteases6, 10. Indeed, telaprevir inhibits some host serine proteases at concentrations that may be achieved in a therapeutic setting14, 16.
The aim of this study was to achieve potent inhibition of viral proteases through covalent bond formation without compromising selectivity of the inhibitors. Our new design strategy used structural bioinformatics to create a structural alignment between viral proteases and host proteases to identify nucleophilic amino acids in the binding site that were unique to the viral proteases. Our structural alignment revealed that current covalent inhibitors such as telaprevir target a catalytic residue that is common across the protease family and therefore susceptible to selectivity issues. In contrast, we identified a nucleophilic amino acid, cysteine 159 (Cys159), in the substrate-binding site that could be targeted for covalent bonding. Importantly, Cys159 is strictly conserved across all 919 HCV NS3 sequences in a database of all known HCVP sequences, including all HCVP subtypes and genotypes sequenced to date (Supplementary Fig. 1), allowing design of a pan-genotype HCVP inhibitor. Although HCVP shows structural similarity with host proteases, Cys159 is structurally unique to HCVP and therefore was an ideal target for achieving selectivity between HCVP and host proteases.
Structure-based drug design was used to create a peptidomimetic inhibitor (1) (Fig. 1a), designed to form canonical reversible interactions with the S2-S1-S1' pockets of HCVP similar to those observed with other reversible peptidomimetic inhibitors12, 17, 18. Further molecular modeling was used to evaluate structures that positioned a low-reactivity Michael acceptor close enough to Cys159 to form a covalent bond (2) (Fig. 1a). 2 was prepared by installation of an acrylamide using a simple glycine linker. Linking the electrophilic acrylamide via a D-alanine linker provides the more conformationally constrained inhibitor 3 (see Supplementary Methods). Our expectation was that propanamide 4, the reversible congener of 3, would bind weakly to the HCVP, as potent inhibitors reported to date typically possess functionality that forms extensive nonbonding interactions with the S3 and S4 pockets.
As predicted, 1 and 4 showed weak inhibition of the wild-type HCVP (half-maximal inhibitory concentration (IC50) of 1 = 2,458 nM, 4 IC50 = 1,147 nM) whereas 2 and 3 were very potent inhibitors (2 IC50 = 4 nM, 3 IC50 = 2 nM) (Supplementary Table 1). To further support the importance of covalency in conferring activity of 3, we tested the activity of 3 against a mutant NS3 protein in which the target cysteine is changed to a serine (C159S). The C159S protease is comparable in enzymatic activity to wild-type protease (Supplementary Fig. 2); however, mutation of the amino acid required for bond formation results in a sharp decrease in potency of the covalent inhibitor (IC50 = 1,782 nM; Supplementary Table 1). In further support of the mechanism, 3 shifted the mass of HCVP by 685 Da, consistent with the formation of a covalent complex between 3 and the protease, but was unable to covalently bond to HCVP with the C159S mutation (Supplementary Fig. 3). We also confirmed with X-ray crystallography that 3 was covalently linked to the side chain of Cys159 (Fig. 1b, Supplementary Fig. 4 and Supplementary Table 2).
The selectivity of 3 was further demonstrated using a panel of host proteases. As expected, 3 showed no notable inhibition of host proteases, whereas telaprevir inhibited multiple host proteases, when each inhibitor was tested at 10 µM (Fig. 2a). Moreover, 3 showed no significant nonspecific reactivity toward glutathione (Supplementary Fig. 5). These data highlight the value of covalent bonding to a noncatalytic residue as a means of achieving HCVP selectivity while minimizing the potential for nonspecific reactivity with other thiols such as glutathione.
Huh-7 wild-type (1b) replicon cells were used to demonstrate that 3 can potently inhibit HCVP activity in cells, leading to decreased replication of viral RNA. Luciferase activity was greatly reduced in cells treated with 3 (half-maximal effective concentration (EC50) = 6 nM) (Fig. 2b and Supplementary Table 1). In contrast, the reversible congener, 4, did not inhibit luciferase activity (EC50 > 3000 nM), demonstrating that covalent bonding greatly enhances potency for this class of compounds. Importantly, 3 does not inhibit proliferation of Huh-7 wild-type replicon cells, nor does it affect growth of other cell lines tested (Supplementary Table 3), strongly suggesting that replicon inhibition is because of specific viral protease inhibition. 3 was inactive in the C159S mutant replicon cells (EC50 > 3,000 nM) and, as expected, the activity of 4 and telaprevir were unchanged by the C159S mutation, as they are not dependent on the cysteine for their mechanism of action (EC50 > 3,000 nM, EC50 = 623nM, respectively) (Fig. 2b and Supplementary Table 1). Of note, the C159S mutant replicon cells showed fitness similar to that of wild-type replicon cells (Supplementary Fig. 6).
Numerous NS3 mutations have been reported that render HCVP resistant to the current protease inhibitors. Thus, activity against drug-resistant clinical mutations is important for effective antiviral therapeutics19. 3 was able to inhibit and bond to HCVP proteins of clinically relevant NS3 variants (Supplementary Table 1 and Supplementary Fig. 7). Furthermore, the selectivity conferred by Cys159 also allows for binding and inhibition of HCVP from multiple genotypes (Supplementary Table 1 and Supplementary Fig. 8), suggesting that this approach will lead to potent and selective pan-genotype HCVP inhibitors.
To demonstrate direct inhibition of HCVP activity using our irreversible covalent drug, we developed an assay using the internal self-cleavage activity of HCVP20 (Supplementary Fig. 9). We confirmed the necessity of HCVP activity in the proteolytic cleavage of NS3/4A by expressing wild-type HCVP or a protease-dead mutant, NS3/4A-S139A (Supplementary Fig. 10). This autoproteolytic cleavage activity was used to directly measure HCVP activity in replicon cells in the presence and absence of the covalent inhibitor. When HCVP activity is inhibited, self-cleavage is abolished, leaving only the full-length holoenzyme. 3 demonstrated inhibition of HCVP internal self-cleavage activity, and the inhibition was sustained for 8-24 h after compound removal. In contrast, HCVP self-cleavage activity had completely returned by 30 min after removal of telaprevir (Supplementary Fig. 11a,b).
A unique advantage of an irreversible covalent molecule is that it allows the investigation of target occupancy in a time- and dose-dependent manner. We designed a biotinylated irreversible covalent probe that bonds to NS3/4A protease (Supplementary Scheme 4), enabling the quantitative analysis of NS3 occupancy with 3, and found that inhibitory activity and NS3-occupancy closely correlate (Fig. 3a,b). Following treatment with 3, there is little or no free NS3 available to bind to the biotinylated probe for at least 8 h after 3 has been removed (Fig. 3b). This indicates that essentially all of the NS3 protein was bound by 3, and newly synthesized protein is being detected at 8-24 h. Return of self-cleavage activity is concomitant with the detection of newly synthesized protease. The biotinylated covalent probe compound is also an indicator of the selectivity of 3, as the two compounds share structural similarities and electrophiles. Only the full-length NS3 protein and NS3/4A cleavage products were detected as having been labeled by the biotinylated probe, indicating that it is specific for NS3/4A under these conditions (Fig. 3c).
A targeted covalent design approach21 has been applied to kinases, several of which are currently in clinical testing with encouraging evidence of efficacy and safety22. This study describes the first successful example of applying targeted covalent inhibition to the protease family. Our data indicate that the electrophile on 3 must be brought into close proximity to a nucleophilic thiol via specific affinity-driven binding to enable covalent bond formation between the small molecule and the targeted HCVP . This strategy enables us to selectively inhibit HCVP and minimize the potential for toxicity through reactivity with off-target proteins. 3 is an excellent prototype HCVP inhibitor but has a number of important limitations as a drug candidate; these properties have been optimized in our current development compounds, AVL-181 and AVL-192, which have excellent pharmacokinetics and bind potently to wild-type HCVP as well as to multiple other genotypes and mutant forms of HCVP, including C159S, but only covalently modify when Cys159 is present23. The successful design of a highly selective targeted covalent inhibitor of HCVP suggests that this approach can be broadly applied to other protease family members and indeed to a wide range of protein families.
Source
Mon, Nov 29, 2010
A new study has demonstrated that irreversible covalent inhibition can increase selectivity, potency and duration of action, broadens applications for targeted covalent drugs to the protease gene family.
Avila Therapeutics Inc., a biotechnology company developing novel targeted covalent drugs, has demonstrated the first-ever selective irreversible inhibition of a viral protease using a targeted covalent drug.
Avila has used its proprietary Avilomics platform to design covalent irreversible protease inhibitors that are highly selective, potent and with superior duration of action as compared to conventional protease inhibitors.
The research has demonstrated that covalent drugs can be designed and targeted to irreversibly and covalently bond to molecular domains specific to proteases.
"This research elevates covalent drug design to a fundamentally new level. By creating extremely selective protease inhibitors with their platform, Avila is showing the remarkable therapeutic potential of irreversible covalent drugs to address a broad spectrum of drug targets," said Simon Campbell , a renowned scientist.
"This approach can make a difference to patients living with HCV infection, and we expect to make an impact in other important areas such as cancer and inflammatory disease," said said Juswinder Singh, co-author of the paper.
In order to maximize selectivity and minimize off-target effects, the irreversible covalent inhibitors of HCV protease were designed to covalently target a unique structure in the HCV protease not found in human proteases. Key findings include:
A representative irreversible covalent inhibitor designed, by Avila, was shown to inhibit the HCV protease (also known as "NS3") in cells at a concentration of 6 nM.
Specific covalent bond formation between the drug and target protease was demonstrated through use of mass spectrometry and also x-ray crystallography.
The findings were published in the journal Nature Chemical Biology. (ANI)
-------------------------------------------
Avila Presents New Data on its Novel, Orally-Available Targeted Covalent Drug, AVL-192
Covalent Inhibition Achieves Superior Potency Against Drug-Resistant HCV Mutants
BOSTON and WALTHAM, MA - November 2, 2010 - Avila TherapeuticsTM, Inc., a biotechnology company developing novel targeted covalent drugs, presented results today of preclinical studies that demonstrate its orally-available targeted covalent drug candidate, AVL-192, achieves superior potency against drug-resistant mutations of the Hepatitis C Virus (HCV). These new data were presented today at the Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) international meeting in Boston, Massachusetts.
HCV protease (also known as NS3) is a promising target of intervention for the treatment of hepatitis C infection. However, medicines currently in late stages of clinical development are vulnerable to drug- resistant mutations. AVL-192 is a novel, orally available compound that can rapidly and completely silence the HCV protease through highly selective, irreversible covalent bonding to the target protein. Preclinical data have demonstrated that AVL-192 achieves very high potency and selectivity for NS3 and also potently and effectively inhibits the drug-resistant mutations observed clinically.
Avila's covalent approach to silencing the NS3 protein has resulted in a product candidate with a potential best-in-class profile due to the ability to retain potency against clinically-arising resistance mutations, and potential breadth of activity across HCV genotypes with anticipated once-per-day dosing.
In a poster presentation at the meeting, entitled, "Second Generation of Covalent Irreversible Inhibitors Have Superior Potency Across Genotypes and Drug Resistant Mutants," data were presented from preclinical studies that evaluated the efficacy of AVL-192 in biochemical and cell culture studies. Highlights of the data demonstrate:
· AVL-192 has a time-dependent mode of action that delivers potent and rapid inhibition of WT NS3/4A and retains high potency against drug-resistant mutant NS3/4A proteases;
· AVL-192 is able to inhibit the protease long after the compound is removed, offering the benefit of less frequent dosing;
· AVL-192 as monotherapy can be curative in the replicon clearance assay;
· AVL-192 is highly selective and spares host proteases; and
· AVL-192 has high plasma exposure following oral administration in rats and dogs.
"These new data reinforce our belief that our targeted covalent drug candidate AVL-192 has the potential to be a best-in-class, pan-genotype HCV therapeutic due to its unique mechanism of action," said Juswinder Singh, Ph.D., Avila's Founder and Chief Scientific Officer.
About Avila TherapeuticsTM, Inc.
Avila focuses on design and development of targeted covalent drugs to achieve best-in-class outcomes that cannot be achieved through traditional chemistries. This approach is called "protein silencing". The company's product pipeline has been built using its proprietary AvilomicsTM platform and is currently focused on viral infection, cancer and autoimmune disease. Avila is funded by leading venture capital firms: Abingworth, Advent Venture Partners, Atlas Venture, Novartis Option Fund, and Polaris Venture Partners. For additional information, please visit http://www.avilatx.com/
------------------------------------
Selective irreversible inhibition of a protease by targeting a noncatalytic cysteine
Brief Communication
Nature Chemical Biology, 28 November 2010
Margit Hagel, Deqiang Niu, Thia St Martin, Michael P Sheets, Lixin Qiao, Hugues Bernard, Russell M Karp, Zhendong Zhu, Matthew T Labenski, Prasoon Chaturvedi, Mariana Nacht, William F Westlin, Russell C Petter & Juswinder Singh 1Avila Therapeutics, Inc., Waltham, Massachusetts, USA. 2Millenium: The Takeda Oncology Company, Cambridge, Massachusetts, USA. *e-mail: jsingh@avilatx.com
Designing selective inhibitors of proteases has proven problematic, in part because pharmacophores that confer potency exploit the conserved catalytic apparatus. We developed a fundamentally different approach by designing irreversible inhibitors that target noncatalytic cysteines that are structurally unique to a target in a protein family. We have successfully applied this approach to the important therapeutic target HCV protease, which has broad implications for the design of other selective protease inhibitors.
The fundamental challenge in designing protease inhibitors is to achieve potency without sacrificing selectivity. This problem arises frequently because the typical protease inhibitor achieves potency through covalent interactions with the catalytic apparatus, yet such pharmacophores also confer affinity for other proteases in the same mechanistic family1. This is a significant challenge for protease drug design, because over 500 proteases exist in the human genome. Achieving selectivity while targeting the catalytic machinery is thus particularly difficult2.
Covalent irreversible drugs that form persistent, nonlabile covalent bonds yield unique therapeutic benefits including rapid onset of inhibition, greater potency, longer duration of drug action and potent and persistent activity against mutations that would otherwise lead to drug resistance3. There are many examples of drugs that work through irreversible covalent bonding that have proven to be safe and successful therapies for a wide variety of indications4. Despite their prevalence, to date covalent drugs have largely been discovered serendipitously, and general methods to facilitate their deliberate discovery and design have yet to be described.
HCV NS3/4A viral protease (HCVP) activity is essential for viral replication5 and has been recently validated as a clinical target6, 7, 8, 9, 10, 11, 12, 13, 14, 15. Protease inhibitors such as telaprevir exemplify the challenges of covalent targeting of the catalytic binding site; upon binding to HCVP, the α-ketoamide forms a reversible covalent linkage with the catalytic serine that is conserved within proteases6, 10. Indeed, telaprevir inhibits some host serine proteases at concentrations that may be achieved in a therapeutic setting14, 16.
The aim of this study was to achieve potent inhibition of viral proteases through covalent bond formation without compromising selectivity of the inhibitors. Our new design strategy used structural bioinformatics to create a structural alignment between viral proteases and host proteases to identify nucleophilic amino acids in the binding site that were unique to the viral proteases. Our structural alignment revealed that current covalent inhibitors such as telaprevir target a catalytic residue that is common across the protease family and therefore susceptible to selectivity issues. In contrast, we identified a nucleophilic amino acid, cysteine 159 (Cys159), in the substrate-binding site that could be targeted for covalent bonding. Importantly, Cys159 is strictly conserved across all 919 HCV NS3 sequences in a database of all known HCVP sequences, including all HCVP subtypes and genotypes sequenced to date (Supplementary Fig. 1), allowing design of a pan-genotype HCVP inhibitor. Although HCVP shows structural similarity with host proteases, Cys159 is structurally unique to HCVP and therefore was an ideal target for achieving selectivity between HCVP and host proteases.
Structure-based drug design was used to create a peptidomimetic inhibitor (1) (Fig. 1a), designed to form canonical reversible interactions with the S2-S1-S1' pockets of HCVP similar to those observed with other reversible peptidomimetic inhibitors12, 17, 18. Further molecular modeling was used to evaluate structures that positioned a low-reactivity Michael acceptor close enough to Cys159 to form a covalent bond (2) (Fig. 1a). 2 was prepared by installation of an acrylamide using a simple glycine linker. Linking the electrophilic acrylamide via a D-alanine linker provides the more conformationally constrained inhibitor 3 (see Supplementary Methods). Our expectation was that propanamide 4, the reversible congener of 3, would bind weakly to the HCVP, as potent inhibitors reported to date typically possess functionality that forms extensive nonbonding interactions with the S3 and S4 pockets.
As predicted, 1 and 4 showed weak inhibition of the wild-type HCVP (half-maximal inhibitory concentration (IC50) of 1 = 2,458 nM, 4 IC50 = 1,147 nM) whereas 2 and 3 were very potent inhibitors (2 IC50 = 4 nM, 3 IC50 = 2 nM) (Supplementary Table 1). To further support the importance of covalency in conferring activity of 3, we tested the activity of 3 against a mutant NS3 protein in which the target cysteine is changed to a serine (C159S). The C159S protease is comparable in enzymatic activity to wild-type protease (Supplementary Fig. 2); however, mutation of the amino acid required for bond formation results in a sharp decrease in potency of the covalent inhibitor (IC50 = 1,782 nM; Supplementary Table 1). In further support of the mechanism, 3 shifted the mass of HCVP by 685 Da, consistent with the formation of a covalent complex between 3 and the protease, but was unable to covalently bond to HCVP with the C159S mutation (Supplementary Fig. 3). We also confirmed with X-ray crystallography that 3 was covalently linked to the side chain of Cys159 (Fig. 1b, Supplementary Fig. 4 and Supplementary Table 2).
The selectivity of 3 was further demonstrated using a panel of host proteases. As expected, 3 showed no notable inhibition of host proteases, whereas telaprevir inhibited multiple host proteases, when each inhibitor was tested at 10 µM (Fig. 2a). Moreover, 3 showed no significant nonspecific reactivity toward glutathione (Supplementary Fig. 5). These data highlight the value of covalent bonding to a noncatalytic residue as a means of achieving HCVP selectivity while minimizing the potential for nonspecific reactivity with other thiols such as glutathione.
Huh-7 wild-type (1b) replicon cells were used to demonstrate that 3 can potently inhibit HCVP activity in cells, leading to decreased replication of viral RNA. Luciferase activity was greatly reduced in cells treated with 3 (half-maximal effective concentration (EC50) = 6 nM) (Fig. 2b and Supplementary Table 1). In contrast, the reversible congener, 4, did not inhibit luciferase activity (EC50 > 3000 nM), demonstrating that covalent bonding greatly enhances potency for this class of compounds. Importantly, 3 does not inhibit proliferation of Huh-7 wild-type replicon cells, nor does it affect growth of other cell lines tested (Supplementary Table 3), strongly suggesting that replicon inhibition is because of specific viral protease inhibition. 3 was inactive in the C159S mutant replicon cells (EC50 > 3,000 nM) and, as expected, the activity of 4 and telaprevir were unchanged by the C159S mutation, as they are not dependent on the cysteine for their mechanism of action (EC50 > 3,000 nM, EC50 = 623nM, respectively) (Fig. 2b and Supplementary Table 1). Of note, the C159S mutant replicon cells showed fitness similar to that of wild-type replicon cells (Supplementary Fig. 6).
Numerous NS3 mutations have been reported that render HCVP resistant to the current protease inhibitors. Thus, activity against drug-resistant clinical mutations is important for effective antiviral therapeutics19. 3 was able to inhibit and bond to HCVP proteins of clinically relevant NS3 variants (Supplementary Table 1 and Supplementary Fig. 7). Furthermore, the selectivity conferred by Cys159 also allows for binding and inhibition of HCVP from multiple genotypes (Supplementary Table 1 and Supplementary Fig. 8), suggesting that this approach will lead to potent and selective pan-genotype HCVP inhibitors.
To demonstrate direct inhibition of HCVP activity using our irreversible covalent drug, we developed an assay using the internal self-cleavage activity of HCVP20 (Supplementary Fig. 9). We confirmed the necessity of HCVP activity in the proteolytic cleavage of NS3/4A by expressing wild-type HCVP or a protease-dead mutant, NS3/4A-S139A (Supplementary Fig. 10). This autoproteolytic cleavage activity was used to directly measure HCVP activity in replicon cells in the presence and absence of the covalent inhibitor. When HCVP activity is inhibited, self-cleavage is abolished, leaving only the full-length holoenzyme. 3 demonstrated inhibition of HCVP internal self-cleavage activity, and the inhibition was sustained for 8-24 h after compound removal. In contrast, HCVP self-cleavage activity had completely returned by 30 min after removal of telaprevir (Supplementary Fig. 11a,b).
A unique advantage of an irreversible covalent molecule is that it allows the investigation of target occupancy in a time- and dose-dependent manner. We designed a biotinylated irreversible covalent probe that bonds to NS3/4A protease (Supplementary Scheme 4), enabling the quantitative analysis of NS3 occupancy with 3, and found that inhibitory activity and NS3-occupancy closely correlate (Fig. 3a,b). Following treatment with 3, there is little or no free NS3 available to bind to the biotinylated probe for at least 8 h after 3 has been removed (Fig. 3b). This indicates that essentially all of the NS3 protein was bound by 3, and newly synthesized protein is being detected at 8-24 h. Return of self-cleavage activity is concomitant with the detection of newly synthesized protease. The biotinylated covalent probe compound is also an indicator of the selectivity of 3, as the two compounds share structural similarities and electrophiles. Only the full-length NS3 protein and NS3/4A cleavage products were detected as having been labeled by the biotinylated probe, indicating that it is specific for NS3/4A under these conditions (Fig. 3c).
A targeted covalent design approach21 has been applied to kinases, several of which are currently in clinical testing with encouraging evidence of efficacy and safety22. This study describes the first successful example of applying targeted covalent inhibition to the protease family. Our data indicate that the electrophile on 3 must be brought into close proximity to a nucleophilic thiol via specific affinity-driven binding to enable covalent bond formation between the small molecule and the targeted HCVP . This strategy enables us to selectively inhibit HCVP and minimize the potential for toxicity through reactivity with off-target proteins. 3 is an excellent prototype HCVP inhibitor but has a number of important limitations as a drug candidate; these properties have been optimized in our current development compounds, AVL-181 and AVL-192, which have excellent pharmacokinetics and bind potently to wild-type HCVP as well as to multiple other genotypes and mutant forms of HCVP, including C159S, but only covalently modify when Cys159 is present23. The successful design of a highly selective targeted covalent inhibitor of HCVP suggests that this approach can be broadly applied to other protease family members and indeed to a wide range of protein families.
Source
EHSI: Celulas Genetica Eyes China for Testing New Stem Cell Procedure
Posted on: Mon, 06 Dec 2010 09:15:00 EST
HOUSTON, Dec 06, 2010 (BUSINESS WIRE) --
Emerging Healthcare Solutions, Inc. (PinkSheets: EHSI
PowerRating) announced today that its newly acquired biotechnology division Celulas Genetica seeks to contract a Chinese firm to test a new stem-cell treatment for liver disease.
Last week, Celulas Genetica purchased a license to develop and market the revolutionary Rutherford Procedure, a groundbreaking organ regeneration treatment intended to utilize proton-beam technology to destroy diseased organ tissue for regeneration using adult stem cells. Celulas Genetica licensed the procedure from a Chinese firm, BBFITCL, and views the emerging Asian superpower as the ideal locale to test and develop its potential new treatment for liver disease.
"China has pushed hard for years to become a world leader in the fields of stem cell research and regenerative medicine," said EHSI President and CEO Cindy Morrissey. "The scientific and medical resources needed to test the Rutherford Procedure are both abundant and affordable in China, and Celulas Genetica is currently exploring the possibility of working with a proton therapy facility there to develop this new treatment for liver disease."
Morrissey said she plans to travel to China soon to meet with Chinese stem-cell researchers and potentially help open a Celulas Genetica business office there. Extending its reach into the R&D hotbed of China would build on EHSI's rapidly expanding global footprint--Celulas Genetica is headquartered in Panama, and Morrissey opened EHSI business offices in Poland and Germany last month.
"Liver disease is a truly global affliction," Morrissey said. "It requires a global solution. Working together with scientists and doctors in Panama, China and elsewhere, we believe we can develop the Rutherford Procedure into an effective, minimally invasive treatment for liver disease that will not require transplants."
Last week, EHSI announced its acquisition of a Rotary Cell Culture System, or bioreactor, developed using revolutionary NASA research in the field of microgravity. Cell cultures, including stem cells, grown inside the bioreactor look and function much closer to human cells grown within the body than cell cultures grown in Petri dishes. During the Rutherford Procedure, proton therapy will be used to destroy scar-tissue cells in the liver using high-energy proton beams, a non-invasive treatment proven to minimize damage to healthy tissues and to eliminate the side effects (including nausea) of traditional radiation therapy.
As the scar tissue is systematically destroyed by the proton therapy, a catheter will deliver the patient's own cultured stem cells directly to his or her liver through the bloodstream. As more and more diseased tissue is destroyed, these cultured stem cells could help regenerate the patient's damaged, cirrhotic liver into a healthy, functioning organ once more.
EHSI invests in technology developed to compete in the stem-cell research industry alongside Dendreon Corp. (NASDAQ: DNDN), Gilead Sciences (NASDAQ: GILD), Celgene Corp. (NASDAQ: CELG) and Biogen Idec Inc. (NASDAQ: BIIB).
About Emerging Healthcare Solutions, Inc.
Emerging Healthcare Solutions, Inc. invests in and participates in the profits of emerging breakthrough medical technologies. The Company believes the secret of leveraging future value for its shareholders is the proper timing of its investment in promising new medical technologies. EHSI aims to capture future profits of promising new medical technologies by investing in these technologies at the inflection point of product development. We believe this model will deliver long-term positive results for our investors.
For more information, please visit http://www.emerginghealthcaresolutionsinc.com/.
Safe Harbor Statement under the Private Securities Litigation Reform Act of 1995: This news release contains forward-looking information within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended, including statements that include the words "believes," "expects," "anticipate" or similar expressions. Such forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause the actual results, performance or achievements of the company to differ materially from those expressed or implied by such forward-looking statements. In addition, description of anyone's past success, either financial or strategic, is no guarantee of future success. This news release speaks as of the date first set forth above and the company assumes no responsibility to update the information included herein for events occurring after the date hereof.
SOURCE: Emerging Healthcare Solutions, Inc.
Emerging Healthcare Solutions, Inc.
Cindy Morrissey, 713-821-1486
President and CEO
Source
HOUSTON, Dec 06, 2010 (BUSINESS WIRE) --
Emerging Healthcare Solutions, Inc. (PinkSheets: EHSI
PowerRating) announced today that its newly acquired biotechnology division Celulas Genetica seeks to contract a Chinese firm to test a new stem-cell treatment for liver disease.
Last week, Celulas Genetica purchased a license to develop and market the revolutionary Rutherford Procedure, a groundbreaking organ regeneration treatment intended to utilize proton-beam technology to destroy diseased organ tissue for regeneration using adult stem cells. Celulas Genetica licensed the procedure from a Chinese firm, BBFITCL, and views the emerging Asian superpower as the ideal locale to test and develop its potential new treatment for liver disease.
"China has pushed hard for years to become a world leader in the fields of stem cell research and regenerative medicine," said EHSI President and CEO Cindy Morrissey. "The scientific and medical resources needed to test the Rutherford Procedure are both abundant and affordable in China, and Celulas Genetica is currently exploring the possibility of working with a proton therapy facility there to develop this new treatment for liver disease."
Morrissey said she plans to travel to China soon to meet with Chinese stem-cell researchers and potentially help open a Celulas Genetica business office there. Extending its reach into the R&D hotbed of China would build on EHSI's rapidly expanding global footprint--Celulas Genetica is headquartered in Panama, and Morrissey opened EHSI business offices in Poland and Germany last month.
"Liver disease is a truly global affliction," Morrissey said. "It requires a global solution. Working together with scientists and doctors in Panama, China and elsewhere, we believe we can develop the Rutherford Procedure into an effective, minimally invasive treatment for liver disease that will not require transplants."
Last week, EHSI announced its acquisition of a Rotary Cell Culture System, or bioreactor, developed using revolutionary NASA research in the field of microgravity. Cell cultures, including stem cells, grown inside the bioreactor look and function much closer to human cells grown within the body than cell cultures grown in Petri dishes. During the Rutherford Procedure, proton therapy will be used to destroy scar-tissue cells in the liver using high-energy proton beams, a non-invasive treatment proven to minimize damage to healthy tissues and to eliminate the side effects (including nausea) of traditional radiation therapy.
As the scar tissue is systematically destroyed by the proton therapy, a catheter will deliver the patient's own cultured stem cells directly to his or her liver through the bloodstream. As more and more diseased tissue is destroyed, these cultured stem cells could help regenerate the patient's damaged, cirrhotic liver into a healthy, functioning organ once more.
EHSI invests in technology developed to compete in the stem-cell research industry alongside Dendreon Corp. (NASDAQ: DNDN), Gilead Sciences (NASDAQ: GILD), Celgene Corp. (NASDAQ: CELG) and Biogen Idec Inc. (NASDAQ: BIIB).
About Emerging Healthcare Solutions, Inc.
Emerging Healthcare Solutions, Inc. invests in and participates in the profits of emerging breakthrough medical technologies. The Company believes the secret of leveraging future value for its shareholders is the proper timing of its investment in promising new medical technologies. EHSI aims to capture future profits of promising new medical technologies by investing in these technologies at the inflection point of product development. We believe this model will deliver long-term positive results for our investors.
For more information, please visit http://www.emerginghealthcaresolutionsinc.com/.
Safe Harbor Statement under the Private Securities Litigation Reform Act of 1995: This news release contains forward-looking information within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended, including statements that include the words "believes," "expects," "anticipate" or similar expressions. Such forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause the actual results, performance or achievements of the company to differ materially from those expressed or implied by such forward-looking statements. In addition, description of anyone's past success, either financial or strategic, is no guarantee of future success. This news release speaks as of the date first set forth above and the company assumes no responsibility to update the information included herein for events occurring after the date hereof.
SOURCE: Emerging Healthcare Solutions, Inc.
Emerging Healthcare Solutions, Inc.
Cindy Morrissey, 713-821-1486
President and CEO
Source
Achillion To Present Data From Studies Of ACH-1625 In Hepatitis C At Asian Pacific Liver Conference
NEW HAVEN, Conn., Dec. 6, 2010 (GLOBE NEWSWIRE) -- Achillion Pharmaceuticals, Inc. (Nasdaq:ACHN) today announced that data from the Company's ongoing clinical studies of ACH-1625 has been accepted for presentation at the 21st Annual Conference of the Asian Pacific Association for the Study of the Liver (APASL 2011) to be held February 17-21, 2011 in Bangkok, Thailand.
ACH-1625 is an inhibitor of HCV NS3 protease that was discovered and is being developed by Achillion.
The presentation, entitled "Viral Kinetics Modeling of Short-term Monotherapy Data of ACH-1625, an HCV Protease Inhibitor," will be presented by Dr. Atul Agarwal, Senior Director of Computational Chemistry of Achillion. (Abstract A-315-0024-00792.) The presentation describes a mathematical analysis of HCV RNA data collected after oral administration of ACH-1625 in HCV genotype 1 infected subjects. This analysis shows rapid and near complete hepatitis C virus clearance following ACH-1625 administration at all dose levels tested. In addition, mathematical modeling of HCV viral kinetics provided information that allowed for subsequent dose selection for Phase II clinical development of ACH-1625.
"These data support and further demonstrate ACH-1625's robust antiviral activity," said Dr. Agarwal. "With clinical data that demonstrated reductions in viral RNA between 3-4.25 log10, these mathematical data quantitatively show the percentage of total virus cleared after five days of ACH-1625 monotherapy. This data also identifies specific patient population characteristics."
"We are pleased to continue to put forward a large body of scientific and clinical data on ACH-1625," commented Michael D. Kishbauch, Chief Executive Officer of Achillion. "We look forward to completing the current Phase II clinical trial of ACH-1625 to further support its profile as a potential best-in-class protease inhibitor for the treatment of HCV."
About ACH-1625
ACH-1625 is an HCV protease inhibitor designed and synthesized based on crystal structures of enzyme/inhibitor complex. ACH-1625 is an open chain, non-covalent, reversible inhibitor of NS3 protease. In preclinical studies, ACH-1625 demonstrated high potency, unique pharmacokinetic properties and an excellent safety profile at high drug exposures. With its rapid and extensive partitioning to the liver, as well as high liver/plasma ratios demonstrated in preclinical studies, Achillion believes that ACH-1625 has the potential for once daily dosing. ACH-1625 has shown low single-digit nanomolar potency that is specific to HCV. It is equipotent against HCV genotypes 1a and 1b at IC50~1nM.
In clinical studies, HCV-infected patients receiving doses ranging from 200 to 600 mg twice daily, and 400 to 600 mg once daily, showed mean maximal reductions in viral load ranging from of 3.07 log10 to 4.25 log10. Furthermore, all patients had viral loads that remained suppressed for at least 7 days after dosing was completed, maintaining a mean reduction of more than 1log10 from baseline through day 12, the last day of viral load measurement in the study.
About HCV
The hepatitis C virus is the most common cause of viral hepatitis, which is an inflammation of the liver. It is currently estimated that more than 170 million people are infected with HCV worldwide and The American Association of Liver Disease estimates that up to 80% of individuals become chronically infected following exposure to the virus. If left untreated, chronic hepatitis can lead to permanent liver damage, which can result in the development of liver cancer, liver failure or death. Few therapeutic options currently exist for the treatment of HCV infection. The current standard of care is limited by its specificity for certain types of HCV, significant side-effect profile, and injectable route of administration.
About Achillion
Achillion is an innovative pharmaceutical company dedicated to bringing important new treatments to patients with infectious disease. Achillion's proven discovery and development teams have advanced multiple product candidates with novel mechanisms of action. Achillion is focused on solutions for the most challenging problems in infectious disease -hepatitis C, resistant bacterial infections and HIV. For more information on Achillion Pharmaceuticals, please visit www.achillion.com or call 1-203-624-7000.
This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including statements with respect to the potency, safety and other characteristics of ACH-1625, which may not be duplicated in future cohorts at different doses or in future clinical studies of longer duration, as well as Achillion's expectations regarding timing and duration of other clinical trials. Among the factors that could cause actual results to differ materially from those indicated by such forward-looking statements are: uncertainties relating to results of clinical trials, unexpected regulatory actions or delays, and Achillion's ability to obtain additional funding required to conduct its research, development and commercialization activities. These and other risks are described in the reports filed by Achillion with the U.S. Securities and Exchange Commission, including its Annual Report on Form 10-K for the fiscal year ended December 31, 2009.
Source
ACH-1625 is an inhibitor of HCV NS3 protease that was discovered and is being developed by Achillion.
The presentation, entitled "Viral Kinetics Modeling of Short-term Monotherapy Data of ACH-1625, an HCV Protease Inhibitor," will be presented by Dr. Atul Agarwal, Senior Director of Computational Chemistry of Achillion. (Abstract A-315-0024-00792.) The presentation describes a mathematical analysis of HCV RNA data collected after oral administration of ACH-1625 in HCV genotype 1 infected subjects. This analysis shows rapid and near complete hepatitis C virus clearance following ACH-1625 administration at all dose levels tested. In addition, mathematical modeling of HCV viral kinetics provided information that allowed for subsequent dose selection for Phase II clinical development of ACH-1625.
"These data support and further demonstrate ACH-1625's robust antiviral activity," said Dr. Agarwal. "With clinical data that demonstrated reductions in viral RNA between 3-4.25 log10, these mathematical data quantitatively show the percentage of total virus cleared after five days of ACH-1625 monotherapy. This data also identifies specific patient population characteristics."
"We are pleased to continue to put forward a large body of scientific and clinical data on ACH-1625," commented Michael D. Kishbauch, Chief Executive Officer of Achillion. "We look forward to completing the current Phase II clinical trial of ACH-1625 to further support its profile as a potential best-in-class protease inhibitor for the treatment of HCV."
About ACH-1625
ACH-1625 is an HCV protease inhibitor designed and synthesized based on crystal structures of enzyme/inhibitor complex. ACH-1625 is an open chain, non-covalent, reversible inhibitor of NS3 protease. In preclinical studies, ACH-1625 demonstrated high potency, unique pharmacokinetic properties and an excellent safety profile at high drug exposures. With its rapid and extensive partitioning to the liver, as well as high liver/plasma ratios demonstrated in preclinical studies, Achillion believes that ACH-1625 has the potential for once daily dosing. ACH-1625 has shown low single-digit nanomolar potency that is specific to HCV. It is equipotent against HCV genotypes 1a and 1b at IC50~1nM.
In clinical studies, HCV-infected patients receiving doses ranging from 200 to 600 mg twice daily, and 400 to 600 mg once daily, showed mean maximal reductions in viral load ranging from of 3.07 log10 to 4.25 log10. Furthermore, all patients had viral loads that remained suppressed for at least 7 days after dosing was completed, maintaining a mean reduction of more than 1log10 from baseline through day 12, the last day of viral load measurement in the study.
About HCV
The hepatitis C virus is the most common cause of viral hepatitis, which is an inflammation of the liver. It is currently estimated that more than 170 million people are infected with HCV worldwide and The American Association of Liver Disease estimates that up to 80% of individuals become chronically infected following exposure to the virus. If left untreated, chronic hepatitis can lead to permanent liver damage, which can result in the development of liver cancer, liver failure or death. Few therapeutic options currently exist for the treatment of HCV infection. The current standard of care is limited by its specificity for certain types of HCV, significant side-effect profile, and injectable route of administration.
About Achillion
Achillion is an innovative pharmaceutical company dedicated to bringing important new treatments to patients with infectious disease. Achillion's proven discovery and development teams have advanced multiple product candidates with novel mechanisms of action. Achillion is focused on solutions for the most challenging problems in infectious disease -hepatitis C, resistant bacterial infections and HIV. For more information on Achillion Pharmaceuticals, please visit www.achillion.com or call 1-203-624-7000.
This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including statements with respect to the potency, safety and other characteristics of ACH-1625, which may not be duplicated in future cohorts at different doses or in future clinical studies of longer duration, as well as Achillion's expectations regarding timing and duration of other clinical trials. Among the factors that could cause actual results to differ materially from those indicated by such forward-looking statements are: uncertainties relating to results of clinical trials, unexpected regulatory actions or delays, and Achillion's ability to obtain additional funding required to conduct its research, development and commercialization activities. These and other risks are described in the reports filed by Achillion with the U.S. Securities and Exchange Commission, including its Annual Report on Form 10-K for the fiscal year ended December 31, 2009.
Source
Research Fuels Hope for Hard-To-Treat Hepatitis C Patients
Released: 12/6/2010 12:00 PM EST
Source: Saint Louis University Medical Center
Newswise — The outlook for patients with hepatitis C continues to improve as results from a clinical trial led by a Saint Louis University researcher found that the drug boceprevir helped cure hard-to-treat patients. The findings were reported at the 61st annual meeting of the American Association for the Study of Liver Disease’s earlier in November.
Bruce R. Bacon, M.D., professor of internal medicine at Saint Louis University School of Medicine and co-principal investigator of the HCV RESPOND-2 study, studied the protease inhibitor, boceprevir, and found that it significantly increased the number of patients whose blood had undetectable levels of the virus.
“These findings are especially significant for patients who don’t respond to initial treatment,” said Bacon. “When the hepatitis C virus is not eliminated, debilitating fatigue and more serious problems can follow.”
Hepatitis C is caused by a virus that is transmitted by contact with blood. The infection may initially be asymptomatic, but for patients who develop chronic hepatitis C infection, inflammation of the liver may develop, leading to fibrosis and cirrhosis (scarring of the liver), as well as other complications including liver cancer and death.
The prognosis varies for patients with chronic hepatitis C. With the current standard therapy, about half fully recover after an initial course of peginterferon and ribavirin anti-viral therapy that may last from six months to a year.
The remaining patients, known as non-responders, may improve with initial treatment but the virus is not eliminated, or may not respond to treatment at all.
For this group, the only current option is to retreat patients with the same or similar drugs, which increases the likelihood of severe treatment side-effects. In addition, researchers have found that the success of treatment depends on the major strain, or genotype, of hepatitis C that a patient has.
The HCV RESPOND-2 study looked at 403 patients with chronic hepatitis C infections with genotype one, the most difficult strain of the virus to treat, who still had significant levels of the virus after being treated with peginterferon and ribavirin, the standard hepatitis C treatment.
"These results are very exciting," Bacon said. “In this study, boceprevir helped cure significantly more patients in 24 weeks of therapy than did treatment with peginterferon and ribavirin alone."
A second study, HCV SPRINT-2, examined patients with hepatitis C with genotype one who had not yet been treated with the standard treatment. They, too, responded well to the drug.
Bacon calls the progress made in treating hepatitis C remarkable.
“We’ve gone from the discovery of the virus in 1989 to where we are now, 22 years later, when we have the ability to cure a large majority of those with hepatitis C,” Bacon said. “It’s a true success story.”
“Drugs like boceprevir are going to revolutionize care of those with hepatitis C.”
The clinical trial was funded by Merck, which expects to begin seeking FDA approval this year.
Established in 1836, Saint Louis University School of Medicine has the distinction of awarding the first medical degree west of the Mississippi River. The school educates physicians and biomedical scientists, conducts medical research, and provides health care on a local, national and international level. Research at the school seeks new cures and treatments in five key areas: cancer, liver disease, heart/lung disease, aging and brain disease, and infectious disease.
Source
Source: Saint Louis University Medical Center
Newswise — The outlook for patients with hepatitis C continues to improve as results from a clinical trial led by a Saint Louis University researcher found that the drug boceprevir helped cure hard-to-treat patients. The findings were reported at the 61st annual meeting of the American Association for the Study of Liver Disease’s earlier in November.
Bruce R. Bacon, M.D., professor of internal medicine at Saint Louis University School of Medicine and co-principal investigator of the HCV RESPOND-2 study, studied the protease inhibitor, boceprevir, and found that it significantly increased the number of patients whose blood had undetectable levels of the virus.
“These findings are especially significant for patients who don’t respond to initial treatment,” said Bacon. “When the hepatitis C virus is not eliminated, debilitating fatigue and more serious problems can follow.”
Hepatitis C is caused by a virus that is transmitted by contact with blood. The infection may initially be asymptomatic, but for patients who develop chronic hepatitis C infection, inflammation of the liver may develop, leading to fibrosis and cirrhosis (scarring of the liver), as well as other complications including liver cancer and death.
The prognosis varies for patients with chronic hepatitis C. With the current standard therapy, about half fully recover after an initial course of peginterferon and ribavirin anti-viral therapy that may last from six months to a year.
The remaining patients, known as non-responders, may improve with initial treatment but the virus is not eliminated, or may not respond to treatment at all.
For this group, the only current option is to retreat patients with the same or similar drugs, which increases the likelihood of severe treatment side-effects. In addition, researchers have found that the success of treatment depends on the major strain, or genotype, of hepatitis C that a patient has.
The HCV RESPOND-2 study looked at 403 patients with chronic hepatitis C infections with genotype one, the most difficult strain of the virus to treat, who still had significant levels of the virus after being treated with peginterferon and ribavirin, the standard hepatitis C treatment.
"These results are very exciting," Bacon said. “In this study, boceprevir helped cure significantly more patients in 24 weeks of therapy than did treatment with peginterferon and ribavirin alone."
A second study, HCV SPRINT-2, examined patients with hepatitis C with genotype one who had not yet been treated with the standard treatment. They, too, responded well to the drug.
Bacon calls the progress made in treating hepatitis C remarkable.
“We’ve gone from the discovery of the virus in 1989 to where we are now, 22 years later, when we have the ability to cure a large majority of those with hepatitis C,” Bacon said. “It’s a true success story.”
“Drugs like boceprevir are going to revolutionize care of those with hepatitis C.”
The clinical trial was funded by Merck, which expects to begin seeking FDA approval this year.
Established in 1836, Saint Louis University School of Medicine has the distinction of awarding the first medical degree west of the Mississippi River. The school educates physicians and biomedical scientists, conducts medical research, and provides health care on a local, national and international level. Research at the school seeks new cures and treatments in five key areas: cancer, liver disease, heart/lung disease, aging and brain disease, and infectious disease.
Source
December 4, 2010
Reliability of transient elastography for the detection of fibrosis in Non-Alcoholic Fatty Liver Disease and chronic viral hepatitis
Journal Of Hepatology
Volume 54, Issue 1, Pages 64-71
Silvia Gaia, Silvia Carenzi, Angela L. Barilli, Elisabetta Bugianesi, Antonina Smedile, Franco Brunello, Alfredo Marzano, Mario Rizzetto
Received 7 January 2010; received in revised form 3 May 2010; accepted 2 June 2010.
Background & Aims
Transient elastography (TE) is validated in chronic hepatitis C (CHC) to evaluate hepatic fibrosis; however, limited data are available in chronic hepatitis B (CHB) and Non-Alcoholic Fatty Liver Disease (NAFLD). This prospective study is aimed to assess the accuracy and the efficacy of TE for the detection of fibrosis in patients with chronic liver disease of different etiology and to evaluate the effect of steatosis on the liver stiffness measurement (LSM).
Methods
TE was performed in 219 consecutive patients with chronic liver disease (35% CHC, 32% CHB, and 33% NAFLD) within 6months of the liver biopsy.
Results
LSM was related to the fibrosis stage in each group (CHC: p=0.596, p<0.001; CHB: p=0.418, p<0.001; NAFLD: p=0.573, p<0.001), but the correlation was less strong in CHB and NAFLD than in CHC patients. In CHB patients with histological cirrhosis (F4), the median stiffness value was almost two times lower than in patients with severe fibrosis (F3). In NAFLD patients with advanced fibrosis (F3) and severe steatosis (>33%), the LSM values were lower than expected and were similar to those of patients with initial fibrosis (F1) and fat <33%. TE underestimated the stage of fibrosis in 75% of patients with F3 and steatosis >33%. At multiple logistic regression analysis, in CHC and CHB patients, LSM was the only predictive variable of severe fibrosis/cirrhosis (OR=1.42, p=0.003 and OR=1.354, p=0.003, respectively), while in NAFLD subjects BMI and AST (OR=1.433, p=0.002 and OR=1.053, p=0.020, respectively) but not LSM were independently related with advanced fibrosis and cirrhosis.
Conclusions
This study confirms that TE can be considered a valid support to detect fibrosis in chronic liver disease related to HCV but it should be interpreted cautiously in CHB and NAFLD patients, where host or disease-related factors may modify its accuracy.
Keywords: Transient elastography, Fibroscan, Liver fibrosis, Viral hepatitis, NAFLD
San Giovanni Battista Hospital, Gastroenterology, C. Bramante 88 10128, Italy
Corresponding author. Tel.: +39 3383153995.
PII: S0168-8278(10)00712-9
doi:10.1016/j.jhep.2010.06.022
© 2010 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved
Source
Volume 54, Issue 1, Pages 64-71
Silvia Gaia, Silvia Carenzi, Angela L. Barilli, Elisabetta Bugianesi, Antonina Smedile, Franco Brunello, Alfredo Marzano, Mario Rizzetto
Received 7 January 2010; received in revised form 3 May 2010; accepted 2 June 2010.
Background & Aims
Transient elastography (TE) is validated in chronic hepatitis C (CHC) to evaluate hepatic fibrosis; however, limited data are available in chronic hepatitis B (CHB) and Non-Alcoholic Fatty Liver Disease (NAFLD). This prospective study is aimed to assess the accuracy and the efficacy of TE for the detection of fibrosis in patients with chronic liver disease of different etiology and to evaluate the effect of steatosis on the liver stiffness measurement (LSM).
Methods
TE was performed in 219 consecutive patients with chronic liver disease (35% CHC, 32% CHB, and 33% NAFLD) within 6months of the liver biopsy.
Results
LSM was related to the fibrosis stage in each group (CHC: p=0.596, p<0.001; CHB: p=0.418, p<0.001; NAFLD: p=0.573, p<0.001), but the correlation was less strong in CHB and NAFLD than in CHC patients. In CHB patients with histological cirrhosis (F4), the median stiffness value was almost two times lower than in patients with severe fibrosis (F3). In NAFLD patients with advanced fibrosis (F3) and severe steatosis (>33%), the LSM values were lower than expected and were similar to those of patients with initial fibrosis (F1) and fat <33%. TE underestimated the stage of fibrosis in 75% of patients with F3 and steatosis >33%. At multiple logistic regression analysis, in CHC and CHB patients, LSM was the only predictive variable of severe fibrosis/cirrhosis (OR=1.42, p=0.003 and OR=1.354, p=0.003, respectively), while in NAFLD subjects BMI and AST (OR=1.433, p=0.002 and OR=1.053, p=0.020, respectively) but not LSM were independently related with advanced fibrosis and cirrhosis.
Conclusions
This study confirms that TE can be considered a valid support to detect fibrosis in chronic liver disease related to HCV but it should be interpreted cautiously in CHB and NAFLD patients, where host or disease-related factors may modify its accuracy.
Keywords: Transient elastography, Fibroscan, Liver fibrosis, Viral hepatitis, NAFLD
San Giovanni Battista Hospital, Gastroenterology, C. Bramante 88 10128, Italy
Corresponding author. Tel.: +39 3383153995.
PII: S0168-8278(10)00712-9
doi:10.1016/j.jhep.2010.06.022
© 2010 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved
Source
Insulin resistance predicts re-treatment failure in an efficacy study of peginterferon-α-2a and ribavirin in HIV/HCV co-infected patients
Journal of Hepatology
Volume 54, Issue 1, Pages 41-47
Marie-Louise C. Vachon 1† , Stephanie H. Factor 2† , Andrea D. Branch 1† , Maria-Isabel Fiel 3† , Maribel Rodriguez-Torres 4† , Norbert Bräu 56† , Richard K. Sterling 7† , Jihad Slim 8† , Andrew H. Talal 9† , Douglas T. Dieterich 1† , Mark S. Sulkowski 10†
Received 19 February 2010; received in revised form 11 June 2010; accepted 16 June 2010.
Background & Aims
Few studies evaluated the efficacy of HCV re-treatment and the predictors of response in HIV/HCV co-infected patients. The role of insulin resistance as a predictor of response in this population is unknown. The aim of this study is to evaluate the safety and efficacy of pegylated interferon-α-2a and ribavirin in re-treatment of HIV/HCV co-infected patients, predictors of sustained virological response, including insulin resistance, and the relationship between insulin resistance and liver histology.
Methods
This prospective, multi-centered study included HIV/HCV co-infected patients with prior interferon-based treatment failure. Patients received pegylated interferon-α-2a and ribavirin for 48weeks. Serum HCV RNA was measured 24weeks post treatment to assess sustained virological response. Insulin resistance was defined as HOMA-IR>2. Correlations between baseline insulin resistance and steatosis, and/or cirrhosis were determined.
Results
Sustained virological response was achieved in 14/96 (15%) patients. 35% of patients with HOMA-IR<2 (6/17) achieved sustained virological response vs 14% (5/36) of those with HOMA-IR between 2–4, and 7% (3/41) of those with HOMA-IR>4 (p=0.01). In multivariable analysis, insulin resistance and log10 HCV RNA were negatively associated with sustained virological response [AOR 0.17; 95% CI 0.05–0.64, p=0.009, and AOR 0.36; 95% CI 0.14–0.93, p=0.04, respectively]. Steatosis and cirrhosis correlated with insulin resistance (p=0.02 and 0.03, respectively) but neither independently predicted sustained virological response. Discontinuations due to severe adverse events occurred in 8% of cases, and 2 patients died of unrelated causes.
Conclusions
In HIV/HCV co-infected patients undergoing re-treatment, sustained virological response rate is low; those patients without insulin resistance are significantly more likely to achieve sustained virological response.
Keywords: Insulin resistance, Hepatitis C virus, Chronic, HIV, Re-treatment, Antiviral therapy, Pegylated interferon alfa-2a, Ribavirin
1 Division of Liver Diseases, Mount Sinai School of Medicine, NY, USA
2 Division of Infectious Diseases, Mount Sinai School of Medicine, NY, USA
3 Department of Pathology, Mount Sinai School of Medicine, NY, USA
4 Fundacion de Investigacion de Diego, San Juan, PR, USA
5 Divisions of Infectious Diseases and Liver Diseases, Mount Sinai School of Medicine, NY, USA
6 Veterans Affairs Medical Center, Bronx, NY, USA
7 Division of Liver Diseases, Virginia Commonwealth University Health Systems, Richmond, VA, USA
8 Division of Infectious Diseases, St-Michael’s Medical Center, NY, USA
9 Division of Gastroenterology and Hepatology and Center for the Study of Hepatitis C, Weill Cornell Medical College, NY, USA
10 Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MA, USA
Corresponding author. Address: Mount Sinai School of Medicine, One, Gustave L. Levy Place, Box 1123, NY 10029, USA. Tel.: +1 212 659 8877; fax: +1 212 659 8377.
† On behalf of Hepatitis Resource Network (HRN)-004.
PII: S0168-8278(10)00715-4
doi:10.1016/j.jhep.2010.06.025
© 2010 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.
Source
Volume 54, Issue 1, Pages 41-47
Marie-Louise C. Vachon 1† , Stephanie H. Factor 2† , Andrea D. Branch 1† , Maria-Isabel Fiel 3† , Maribel Rodriguez-Torres 4† , Norbert Bräu 56† , Richard K. Sterling 7† , Jihad Slim 8† , Andrew H. Talal 9† , Douglas T. Dieterich 1† , Mark S. Sulkowski 10†
Received 19 February 2010; received in revised form 11 June 2010; accepted 16 June 2010.
Background & Aims
Few studies evaluated the efficacy of HCV re-treatment and the predictors of response in HIV/HCV co-infected patients. The role of insulin resistance as a predictor of response in this population is unknown. The aim of this study is to evaluate the safety and efficacy of pegylated interferon-α-2a and ribavirin in re-treatment of HIV/HCV co-infected patients, predictors of sustained virological response, including insulin resistance, and the relationship between insulin resistance and liver histology.
Methods
This prospective, multi-centered study included HIV/HCV co-infected patients with prior interferon-based treatment failure. Patients received pegylated interferon-α-2a and ribavirin for 48weeks. Serum HCV RNA was measured 24weeks post treatment to assess sustained virological response. Insulin resistance was defined as HOMA-IR>2. Correlations between baseline insulin resistance and steatosis, and/or cirrhosis were determined.
Results
Sustained virological response was achieved in 14/96 (15%) patients. 35% of patients with HOMA-IR<2 (6/17) achieved sustained virological response vs 14% (5/36) of those with HOMA-IR between 2–4, and 7% (3/41) of those with HOMA-IR>4 (p=0.01). In multivariable analysis, insulin resistance and log10 HCV RNA were negatively associated with sustained virological response [AOR 0.17; 95% CI 0.05–0.64, p=0.009, and AOR 0.36; 95% CI 0.14–0.93, p=0.04, respectively]. Steatosis and cirrhosis correlated with insulin resistance (p=0.02 and 0.03, respectively) but neither independently predicted sustained virological response. Discontinuations due to severe adverse events occurred in 8% of cases, and 2 patients died of unrelated causes.
Conclusions
In HIV/HCV co-infected patients undergoing re-treatment, sustained virological response rate is low; those patients without insulin resistance are significantly more likely to achieve sustained virological response.
Keywords: Insulin resistance, Hepatitis C virus, Chronic, HIV, Re-treatment, Antiviral therapy, Pegylated interferon alfa-2a, Ribavirin
1 Division of Liver Diseases, Mount Sinai School of Medicine, NY, USA
2 Division of Infectious Diseases, Mount Sinai School of Medicine, NY, USA
3 Department of Pathology, Mount Sinai School of Medicine, NY, USA
4 Fundacion de Investigacion de Diego, San Juan, PR, USA
5 Divisions of Infectious Diseases and Liver Diseases, Mount Sinai School of Medicine, NY, USA
6 Veterans Affairs Medical Center, Bronx, NY, USA
7 Division of Liver Diseases, Virginia Commonwealth University Health Systems, Richmond, VA, USA
8 Division of Infectious Diseases, St-Michael’s Medical Center, NY, USA
9 Division of Gastroenterology and Hepatology and Center for the Study of Hepatitis C, Weill Cornell Medical College, NY, USA
10 Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MA, USA
Corresponding author. Address: Mount Sinai School of Medicine, One, Gustave L. Levy Place, Box 1123, NY 10029, USA. Tel.: +1 212 659 8877; fax: +1 212 659 8377.
† On behalf of Hepatitis Resource Network (HRN)-004.
PII: S0168-8278(10)00715-4
doi:10.1016/j.jhep.2010.06.025
© 2010 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.
Source
Elastography for the diagnosis of severity of fibrosis in chronic liver disease: A meta-analysis of diagnostic accuracy
Articles in Press
E.A. Tsochatzis 1, K.S. Gurusamy 2, S. Ntaoula 1, E. Cholongitas 1, B.R. Davidson 2, A.K. Burroughs 1
Received 11 March 2010; received in revised form 16 July 2010; accepted 20 July 2010. published online 30 November 2010.
Uncorrected Proof
Background & Aims
Transient elastography is a non-invasive method of assessing hepatic fibrosis developed as an alternative to liver biopsy. We assessed the performance of elastography for diagnosis of fibrosis using meta-analysis.
Methods
MEDLINE, EMBASE, SCI, Cochrane Library, conference abstracts books, and article references were searched. We included studies using biopsy as a reference standard, with the data necessary to calculate the true and false positive, true and false negative diagnostic results of elastography for a fibrosis stage, and with a 3-month maximum interval between tests. Quality of studies was rated with the QUADAS tool.
Results
We identified 40 eligible studies. Summary sensitivity and specificity was 0.79 (95% CI 0.74–0.82) and 0.78 (95% CI 0.72–0.83) for F2 stage and 0.83 (95% CI 0.79–0.86) and 0.89 (95% CI 0.87–0.91) for cirrhosis. After an elastography result at/over the threshold value for F2 or cirrhosis (“positive” result), the corresponding post-test probability for their presence (if pre-test probability was 50%) was 78%, and 88% respectively, while if values were below these thresholds (“negative” result) the post-test probability was 21% and 16%, respectively. No optimal stiffness cut-offs for individual fibrosis stages were validated in independent cohorts and cut-offs had a wide range and overlap within and between stages.
Conclusion
Elastography theoretically has good sensitivity and specificity for cirrhosis (and less for lesser degrees of fibrosis); however, it should be cautiously applied to everyday clinical practice because there is no validation of the stiffness cut-offs for the various stages. Such validation is required before elastography is considered sufficiently accurate for non-invasive staging of fibrosis.
1 The Royal Free Sheila Sherlock Liver Centre and Division of Surgery, Royal Free Hospital, London NW3 2QG, UK
2 University Department of Surgery, Royal Free Hospital, London NW3 2QG, UK
Corresponding author. Address: The Royal Free Sheila Sherlock Liver Centre and Division of Surgery, Royal Free Hospital, Pond Street, Hampstead, London NW3 2QG, UK. Tel.: +44 2074726229; fax: +44 2074726226.
PII: S0168-8278(10)00825-1
doi:10.1016/j.jhep.2010.07.033
© 2010 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.
Source
E.A. Tsochatzis 1, K.S. Gurusamy 2, S. Ntaoula 1, E. Cholongitas 1, B.R. Davidson 2, A.K. Burroughs 1
Received 11 March 2010; received in revised form 16 July 2010; accepted 20 July 2010. published online 30 November 2010.
Uncorrected Proof
Background & Aims
Transient elastography is a non-invasive method of assessing hepatic fibrosis developed as an alternative to liver biopsy. We assessed the performance of elastography for diagnosis of fibrosis using meta-analysis.
Methods
MEDLINE, EMBASE, SCI, Cochrane Library, conference abstracts books, and article references were searched. We included studies using biopsy as a reference standard, with the data necessary to calculate the true and false positive, true and false negative diagnostic results of elastography for a fibrosis stage, and with a 3-month maximum interval between tests. Quality of studies was rated with the QUADAS tool.
Results
We identified 40 eligible studies. Summary sensitivity and specificity was 0.79 (95% CI 0.74–0.82) and 0.78 (95% CI 0.72–0.83) for F2 stage and 0.83 (95% CI 0.79–0.86) and 0.89 (95% CI 0.87–0.91) for cirrhosis. After an elastography result at/over the threshold value for F2 or cirrhosis (“positive” result), the corresponding post-test probability for their presence (if pre-test probability was 50%) was 78%, and 88% respectively, while if values were below these thresholds (“negative” result) the post-test probability was 21% and 16%, respectively. No optimal stiffness cut-offs for individual fibrosis stages were validated in independent cohorts and cut-offs had a wide range and overlap within and between stages.
Conclusion
Elastography theoretically has good sensitivity and specificity for cirrhosis (and less for lesser degrees of fibrosis); however, it should be cautiously applied to everyday clinical practice because there is no validation of the stiffness cut-offs for the various stages. Such validation is required before elastography is considered sufficiently accurate for non-invasive staging of fibrosis.
1 The Royal Free Sheila Sherlock Liver Centre and Division of Surgery, Royal Free Hospital, London NW3 2QG, UK
2 University Department of Surgery, Royal Free Hospital, London NW3 2QG, UK
Corresponding author. Address: The Royal Free Sheila Sherlock Liver Centre and Division of Surgery, Royal Free Hospital, Pond Street, Hampstead, London NW3 2QG, UK. Tel.: +44 2074726229; fax: +44 2074726226.
PII: S0168-8278(10)00825-1
doi:10.1016/j.jhep.2010.07.033
© 2010 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.
Source
Induction Pegylated Interferon Alfa-2a and High Dose Ribavirin Do Not Increase SVR in Heavy Patients With HCV Genotype 1 and High Viral Loads
Gastroenterology
Volume 139, Issue 6 , Pages 1972-1983, December 2010
K. Rajender Reddy, Mitchell L. Shiffman, Maribel Rodriguez–Torres, Hugo Cheinquer, Djamal Abdurakhmanov, Igor Bakulin, Viacheslav Morozov, Giovanni Faria Silva, Natalia Geyvandova, Carol Stanciu, Michael Rabbia, Michael McKenna, James A. Thommes, Stephen A. Harrison, PROGRESS Study Investigators
Received 28 May 2010; accepted 17 August 2010. published online 06 September 2010.
Abstract
Background & Aims
Patients infected with hepatitis C virus (HCV) genotype 1, body weight ≥85 kg, and high baseline viral load respond poorly to standard doses of pegylated interferon (peginterferon) and ribavirin. We evaluated intensified therapy with peginterferon alfa-2a plus ribavirin.
Methods
This double-blind randomized trial included HCV genotype 1-infected outpatients from hepatology clinics with body weight ≥85 kg and HCV RNA titer ≥400,000 IU/mL. Patients were randomized to 180 μg/wk peginterferon alfa-2a for 48 weeks plus 1200 mg/day ribavirin (standard of care) (group A, n = 191) or 1400/1600 mg/day ribavirin (group B, n = 189). Additional groups included 360 μg/wk peginterferon alfa-2a for 12 weeks then 180 μg/wk peginterferon alfa-2a for 36 weeks plus 1200 mg/day ribavirin (group C, n = 382) or 1400/1600 mg/day ribavirin (group D, n = 383). Follow-up lasted 24 weeks after treatment.
Results
Sustained virologic response rates (HCV RNA level <15 IU/mL at end of follow-up) in groups A, B, C, and D were 38%, 43%, 44%, and 41%, respectively. There were no significant differences among the 4 groups or between pooled peginterferon alfa-2a regimens (A + B vs C + D: odds ratio [OR], 1.08; 95% confidence interval [CI], 0.83–1.39; P = .584) or pooled ribavirin regimens (A + C vs B + D: OR, 1.00; 95% CI, 0.79–1.28; P = .974).
Conclusions
In patients infected with HCV genotype 1 who are difficult to treat (high viral load, body weight ≥85 kg), a 12-week induction regimen of peginterferon alfa-2a and/or higher-dose ribavirin is not more effective than the standard regimen.
Keywords: Chronic Hepatitis C, Tolerability of High-Dose Pegylated Interferon, Steatosis and Response to HCV Therapy, Tolerability of High-Dose Ribavirin
Source
Volume 139, Issue 6 , Pages 1972-1983, December 2010
K. Rajender Reddy, Mitchell L. Shiffman, Maribel Rodriguez–Torres, Hugo Cheinquer, Djamal Abdurakhmanov, Igor Bakulin, Viacheslav Morozov, Giovanni Faria Silva, Natalia Geyvandova, Carol Stanciu, Michael Rabbia, Michael McKenna, James A. Thommes, Stephen A. Harrison, PROGRESS Study Investigators
Received 28 May 2010; accepted 17 August 2010. published online 06 September 2010.
Abstract
Background & Aims
Patients infected with hepatitis C virus (HCV) genotype 1, body weight ≥85 kg, and high baseline viral load respond poorly to standard doses of pegylated interferon (peginterferon) and ribavirin. We evaluated intensified therapy with peginterferon alfa-2a plus ribavirin.
Methods
This double-blind randomized trial included HCV genotype 1-infected outpatients from hepatology clinics with body weight ≥85 kg and HCV RNA titer ≥400,000 IU/mL. Patients were randomized to 180 μg/wk peginterferon alfa-2a for 48 weeks plus 1200 mg/day ribavirin (standard of care) (group A, n = 191) or 1400/1600 mg/day ribavirin (group B, n = 189). Additional groups included 360 μg/wk peginterferon alfa-2a for 12 weeks then 180 μg/wk peginterferon alfa-2a for 36 weeks plus 1200 mg/day ribavirin (group C, n = 382) or 1400/1600 mg/day ribavirin (group D, n = 383). Follow-up lasted 24 weeks after treatment.
Results
Sustained virologic response rates (HCV RNA level <15 IU/mL at end of follow-up) in groups A, B, C, and D were 38%, 43%, 44%, and 41%, respectively. There were no significant differences among the 4 groups or between pooled peginterferon alfa-2a regimens (A + B vs C + D: odds ratio [OR], 1.08; 95% confidence interval [CI], 0.83–1.39; P = .584) or pooled ribavirin regimens (A + C vs B + D: OR, 1.00; 95% CI, 0.79–1.28; P = .974).
Conclusions
In patients infected with HCV genotype 1 who are difficult to treat (high viral load, body weight ≥85 kg), a 12-week induction regimen of peginterferon alfa-2a and/or higher-dose ribavirin is not more effective than the standard regimen.
Keywords: Chronic Hepatitis C, Tolerability of High-Dose Pegylated Interferon, Steatosis and Response to HCV Therapy, Tolerability of High-Dose Ribavirin
Source
Factors associated with sustained virological response in liver transplant recipients with recurrent hepatitis C
Transplant Proc. 2010 Nov;42(9):3647-51.
Pillai AA, Lee VS, Wang E, Rinella ME, Levitsky J.
Abstract
BACKGROUND: Antiviral therapy has achieved sustained virological response (SVR) in less than one third of orthotopic liver transplantation (OLT) patients with recurrent hepatitis C.
AIM: The aim of this study was to identify predictors of SVR in OLT patients treated with pegylated interferon and ribavirin (PEG+RBV) for recurrent hepatitis C virus (HCV).
METHODS: We analyzed data from our transplantation database for 62 subjects treated with PEG+RBV between August 2001 and September 2008. After univariate examination for factors known to be associated with SVR, significant associations (P < .05) were probed using multivariate logistic regression. Kaplan-Meier patient and graft survival analyses were compared between patients with (n = 19; 30.6%) versus without SVR.
RESULTS: On univariate analysis, longer duration of therapy, low pretreatment HCV RNA (<1 million IU/mL), and early virological response (EVR) were associated with SVR. On multivariate analysis, only low pretreatment HCV RNA predicted SVR. Patient survival was significantly higher in the SVR group.
CONCLUSIONS: Covariates associated with SVR among OLT patients with recurrent HCV were similar to the pretransplantation group. Potentially modifiable risk factors, such as obesity, diabetes mellitus, and metabolic syndrome, were not significant predictors of treatment response. Patient survival was associated with SVR, highlighting the impact of successful HCV therapy on long-term post-OLT outcomes.
Copyright © 2010 Elsevier Inc. All rights reserved.
PMID: 21094833 [PubMed - in process]
Source
Pillai AA, Lee VS, Wang E, Rinella ME, Levitsky J.
Abstract
BACKGROUND: Antiviral therapy has achieved sustained virological response (SVR) in less than one third of orthotopic liver transplantation (OLT) patients with recurrent hepatitis C.
AIM: The aim of this study was to identify predictors of SVR in OLT patients treated with pegylated interferon and ribavirin (PEG+RBV) for recurrent hepatitis C virus (HCV).
METHODS: We analyzed data from our transplantation database for 62 subjects treated with PEG+RBV between August 2001 and September 2008. After univariate examination for factors known to be associated with SVR, significant associations (P < .05) were probed using multivariate logistic regression. Kaplan-Meier patient and graft survival analyses were compared between patients with (n = 19; 30.6%) versus without SVR.
RESULTS: On univariate analysis, longer duration of therapy, low pretreatment HCV RNA (<1 million IU/mL), and early virological response (EVR) were associated with SVR. On multivariate analysis, only low pretreatment HCV RNA predicted SVR. Patient survival was significantly higher in the SVR group.
CONCLUSIONS: Covariates associated with SVR among OLT patients with recurrent HCV were similar to the pretransplantation group. Potentially modifiable risk factors, such as obesity, diabetes mellitus, and metabolic syndrome, were not significant predictors of treatment response. Patient survival was associated with SVR, highlighting the impact of successful HCV therapy on long-term post-OLT outcomes.
Copyright © 2010 Elsevier Inc. All rights reserved.
PMID: 21094833 [PubMed - in process]
Source
Importance of hepatitis vaccination in patients with chronic liver disease
South Med J. 2010 Dec;103(12):1223-31.
Kumar M, Herrera JL.
From the Division of Gastroenterology, University of South Alabama College of Medicine, Mobile, AL.
Abstract
Acute hepatitis A or B infection can be lethal in patients with chronic liver disease. Safe and effective vaccines are currently available to prevent hepatitis A and B. Despite wide availability of vaccines, most patients with chronic liver disease are not immunized, in part due to nonuniform and inconsistent current recommendations for this population. A better understanding of the importance of preventing acute hepatitis A and B in patients with chronic liver disease and a proactive approach to vaccination by primary care physicians can positively influence the outcome of patients with chronic liver disease.
PMID: 21057383 [PubMed - in process]
Source
Kumar M, Herrera JL.
From the Division of Gastroenterology, University of South Alabama College of Medicine, Mobile, AL.
Abstract
Acute hepatitis A or B infection can be lethal in patients with chronic liver disease. Safe and effective vaccines are currently available to prevent hepatitis A and B. Despite wide availability of vaccines, most patients with chronic liver disease are not immunized, in part due to nonuniform and inconsistent current recommendations for this population. A better understanding of the importance of preventing acute hepatitis A and B in patients with chronic liver disease and a proactive approach to vaccination by primary care physicians can positively influence the outcome of patients with chronic liver disease.
PMID: 21057383 [PubMed - in process]
Source
Assessment of liver fibrosis before and after antiviral therapy by different serum marker panels in patients with chronic hepatitis C
Alimentary Pharmacology & Therapeutics
Early View (Articles online in advance of print)
S. M. Martinez 1, G. Fernández-Varo 2, P. González 1, E. Sampson 3, M. Bruguera 1, M. Navasa 1, W. Jiménez 2, J. M. Sánchez-Tapias 1, X. Forns 1
Article first published online: 26 OCT 2010
DOI: 10.1111/j.1365-2036.2010.04500.x
© 2010 Blackwell Publishing Ltd
Author Information
1 Liver Unit, Hospital Clinic, IDIBAPS and Ciberehd, Barcelona, Spain.
2 Department of Biochemistry and Molecular Genetics, Hospital Clinic, IDIBAPS and Ciberehd, Barcelona, Spain.
3 Siemens Healthcare Diagnostics, Tarrytown, NY, USA.
*Correspondence: Dr X. Forns, Liver Unit, Hospital Clinic, IDIBAPS and Ciberehd, Villarroel 170, Barcelona 08036, Spain. E-mail: xforns@clinic.ub.es
Abstract
Summary
Background Liver biopsy is the reference standard to assess liver fibrosis in chronic hepatitis C.
Aim To validate and compare the diagnostic performance of non-invasive tests for prediction of liver fibrosis severity and assessed changes in extracellular matrix markers after antiviral treatment.
Methods The performances of Forns’ score, AST to platelet ratio index (APRI), FIB-4 index and Enhanced Liver Fibrosis (ELF) score were validated in 340 patients who underwent antiviral therapy. These scores were determined 24 weeks after treatment in 161 patients.
Results Forns’ score, APRI, FIB-4 and ELF score showed comparable diagnostic accuracies for significant fibrosis [area under the receiver operating characteristic curve (AUROC) 0.83, 0.83, 0.85 and 0.81, respectively]. To identify cirrhosis, FIB-4 index showed a significantly better performance over APRI and ELF score (AUROC 0.89 vs. 0.83 and 0.82, respectively). ELF score decreased significantly in patients with sustained virological response (SVR) (P < 0.0001) but remained unchanged in nonresponders. Non-1 hepatitis C virus (HCV) genotype, baseline lower HCV RNA, glucose, hyaluronic acid and higher cholesterol levels were independently associated with SVR.
Conclusions Simple panel markers and ELF score are accurate at identifying significant fibrosis and cirrhosis in chronic hepatitis C. A decrease in ELF score after antiviral treatment reflects the impact of viral clearance in hepatic extracellular matrix and probably in the improvement of liver fibrosis.
Source
Early View (Articles online in advance of print)
S. M. Martinez 1, G. Fernández-Varo 2, P. González 1, E. Sampson 3, M. Bruguera 1, M. Navasa 1, W. Jiménez 2, J. M. Sánchez-Tapias 1, X. Forns 1
Article first published online: 26 OCT 2010
DOI: 10.1111/j.1365-2036.2010.04500.x
© 2010 Blackwell Publishing Ltd
Author Information
1 Liver Unit, Hospital Clinic, IDIBAPS and Ciberehd, Barcelona, Spain.
2 Department of Biochemistry and Molecular Genetics, Hospital Clinic, IDIBAPS and Ciberehd, Barcelona, Spain.
3 Siemens Healthcare Diagnostics, Tarrytown, NY, USA.
*Correspondence: Dr X. Forns, Liver Unit, Hospital Clinic, IDIBAPS and Ciberehd, Villarroel 170, Barcelona 08036, Spain. E-mail: xforns@clinic.ub.es
Abstract
Summary
Background Liver biopsy is the reference standard to assess liver fibrosis in chronic hepatitis C.
Aim To validate and compare the diagnostic performance of non-invasive tests for prediction of liver fibrosis severity and assessed changes in extracellular matrix markers after antiviral treatment.
Methods The performances of Forns’ score, AST to platelet ratio index (APRI), FIB-4 index and Enhanced Liver Fibrosis (ELF) score were validated in 340 patients who underwent antiviral therapy. These scores were determined 24 weeks after treatment in 161 patients.
Results Forns’ score, APRI, FIB-4 and ELF score showed comparable diagnostic accuracies for significant fibrosis [area under the receiver operating characteristic curve (AUROC) 0.83, 0.83, 0.85 and 0.81, respectively]. To identify cirrhosis, FIB-4 index showed a significantly better performance over APRI and ELF score (AUROC 0.89 vs. 0.83 and 0.82, respectively). ELF score decreased significantly in patients with sustained virological response (SVR) (P < 0.0001) but remained unchanged in nonresponders. Non-1 hepatitis C virus (HCV) genotype, baseline lower HCV RNA, glucose, hyaluronic acid and higher cholesterol levels were independently associated with SVR.
Conclusions Simple panel markers and ELF score are accurate at identifying significant fibrosis and cirrhosis in chronic hepatitis C. A decrease in ELF score after antiviral treatment reflects the impact of viral clearance in hepatic extracellular matrix and probably in the improvement of liver fibrosis.
Source
Silymarin use and liver disease progression in the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis trial
Alimentary Pharmacology & Therapeutics
Early View (Articles online in advance of print)
N. D. Freedman 1, T. M. Curto 2, C. Morishima 3, L. B. Seeff 4, Z. D. Goodman 5, E. C. Wright 6, R. Sinha 1, J. E. Everhart 7, the HALT-C Trial Group 1
Article first published online: 2 NOV 2010
DOI: 10.1111/j.1365-2036.2010.04503.x
Published 2010. This article is a US Government work and is in the public domain in the USA.
Author Information
1 Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Rockville, MD, USA.
2 New England Research Institutes, Watertown, MA, USA.
3 Division of Virology, Department of Laboratory Medicine, University of Washington, Seattle, WA, USA.
4 Division of Digestive Diseases and Nutrition, and Liver Diseases Branch, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
5 Division of Hepatic Pathology, Armed Forces Institute of Pathology, Washington, DC, USA.
6 Office of the Director, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
7 Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
* Correspondence: Dr N. D. Freedman, Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Blvd, EPS/320, MSC 7232, Rockville, MD 20852, USA. E-mail: freedmanne@mail.nih.gov
Abstract
Summary
Background Silymarin is the most commonly used herbal product for chronic liver disease; yet, whether silymarin protects against liver disease progression remains unclear.
Aim To assess the effects of silymarin use on subsequent liver disease progression in 1049 patients of the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) trial who had advanced fibrosis or cirrhosis and had failed prior peginterferon plus ribavirin treatment.
Methods Patients recorded their use of silymarin at baseline and were followed up for liver disease progression (two point increase in Ishak fibrosis score across baseline, year 1.5, and year 3.5 biopsies) and over 8.65 years for clinical outcomes.
Results At baseline, 34% of patients had used silymarin, half of whom were current users. Use of silymarin was associated (P < 0.05) with male gender; oesophageal varices; higher ALT and albumin; and lower AST/ALT ratio, among other features. Baseline users had less hepatic collagen content on study biopsies and had less histological progression (HR: 0.57, 95% CI: 0.33–1.00; P-trend for longer duration of use=0.026). No effect was seen for clinical outcomes.
Conclusions Silymarin use among patients with advanced hepatitis C-related liver disease is associated with reduced progression from fibrosis to cirrhosis, but has no impact on clinical outcomes (Clinicaltrials.gov #NCT00006164).
Source
Early View (Articles online in advance of print)
N. D. Freedman 1, T. M. Curto 2, C. Morishima 3, L. B. Seeff 4, Z. D. Goodman 5, E. C. Wright 6, R. Sinha 1, J. E. Everhart 7, the HALT-C Trial Group 1
Article first published online: 2 NOV 2010
DOI: 10.1111/j.1365-2036.2010.04503.x
Published 2010. This article is a US Government work and is in the public domain in the USA.
Author Information
1 Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Rockville, MD, USA.
2 New England Research Institutes, Watertown, MA, USA.
3 Division of Virology, Department of Laboratory Medicine, University of Washington, Seattle, WA, USA.
4 Division of Digestive Diseases and Nutrition, and Liver Diseases Branch, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
5 Division of Hepatic Pathology, Armed Forces Institute of Pathology, Washington, DC, USA.
6 Office of the Director, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
7 Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
* Correspondence: Dr N. D. Freedman, Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Blvd, EPS/320, MSC 7232, Rockville, MD 20852, USA. E-mail: freedmanne@mail.nih.gov
Abstract
Summary
Background Silymarin is the most commonly used herbal product for chronic liver disease; yet, whether silymarin protects against liver disease progression remains unclear.
Aim To assess the effects of silymarin use on subsequent liver disease progression in 1049 patients of the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) trial who had advanced fibrosis or cirrhosis and had failed prior peginterferon plus ribavirin treatment.
Methods Patients recorded their use of silymarin at baseline and were followed up for liver disease progression (two point increase in Ishak fibrosis score across baseline, year 1.5, and year 3.5 biopsies) and over 8.65 years for clinical outcomes.
Results At baseline, 34% of patients had used silymarin, half of whom were current users. Use of silymarin was associated (P < 0.05) with male gender; oesophageal varices; higher ALT and albumin; and lower AST/ALT ratio, among other features. Baseline users had less hepatic collagen content on study biopsies and had less histological progression (HR: 0.57, 95% CI: 0.33–1.00; P-trend for longer duration of use=0.026). No effect was seen for clinical outcomes.
Conclusions Silymarin use among patients with advanced hepatitis C-related liver disease is associated with reduced progression from fibrosis to cirrhosis, but has no impact on clinical outcomes (Clinicaltrials.gov #NCT00006164).
Source
New York City widens pool of kidney donors
NEW YORK
Wed Dec 1, 2010 11:47am EST
NEW YORK (Reuters) - New York City is changing its kidney donors program to allow organs to be recovered from people who die of heart attacks outside hospitals.
The pilot program, launched on Wednesday by New York City Mayor Michael Bloomberg and the New York Organ Donation Network, overrides rules that restrict the donation of kidneys to cardiac arrest victims who died inside hospitals.
"This new pilot program will help us test a process that could transform the way we donate organs and help save many lives," Bloomberg said in a statement.
Under the program, an Organ Preservation Team will respond to cases of cardiac arrest when an organ donor card is found, or if the deceased is a registered donor. Bodies will then be moved by ambulance to Bellevue hospital for final next-of-kin consent and the transplant operation.
"We are hopeful that it will prove to be an effective and efficient way of honoring donor wishes and making more organs available for life-saving transplants," said Health and Hospitals Corporation President and CEO Alan Aviles.
New York City Fire Commissioner Salvatore Cassano said the new program would benefit both those receiving new organs and those who wished to donate at the time of their death.
The program is funded with a $1.5 million grant from the Department of Health Resources and Services Administration. The pilot program covers Manhattan and runs until May when it will be reviewed for possible expansion.
According to city officials, nearly 8,000 New Yorkers are awaiting organ transplants. Nationally, over 109,000 are waiting for organs, a list to which a new name is added every 13 minutes. Approximately 6,500 people die each year because a transplant is not available.
(Reporting by Bernd Debusmann Jr.; Editing by Mark Egan and Jerry Norton)
Source
Wed Dec 1, 2010 11:47am EST
NEW YORK (Reuters) - New York City is changing its kidney donors program to allow organs to be recovered from people who die of heart attacks outside hospitals.
The pilot program, launched on Wednesday by New York City Mayor Michael Bloomberg and the New York Organ Donation Network, overrides rules that restrict the donation of kidneys to cardiac arrest victims who died inside hospitals.
"This new pilot program will help us test a process that could transform the way we donate organs and help save many lives," Bloomberg said in a statement.
Under the program, an Organ Preservation Team will respond to cases of cardiac arrest when an organ donor card is found, or if the deceased is a registered donor. Bodies will then be moved by ambulance to Bellevue hospital for final next-of-kin consent and the transplant operation.
"We are hopeful that it will prove to be an effective and efficient way of honoring donor wishes and making more organs available for life-saving transplants," said Health and Hospitals Corporation President and CEO Alan Aviles.
New York City Fire Commissioner Salvatore Cassano said the new program would benefit both those receiving new organs and those who wished to donate at the time of their death.
The program is funded with a $1.5 million grant from the Department of Health Resources and Services Administration. The pilot program covers Manhattan and runs until May when it will be reviewed for possible expansion.
According to city officials, nearly 8,000 New Yorkers are awaiting organ transplants. Nationally, over 109,000 are waiting for organs, a list to which a new name is added every 13 minutes. Approximately 6,500 people die each year because a transplant is not available.
(Reporting by Bernd Debusmann Jr.; Editing by Mark Egan and Jerry Norton)
Source
Anemia in Treated-HCV Patients Bodes Well for Sustained Virologic Response
NEW YORK (Reuters Health) Dec 01 - Anemia that develops in patients infected with hepatitis C virus (HCV) during treatment with peginterferon-alfa and ribavirin (PEG-IFN/RBV) may be a good sign, new research hints.
In a large study, researchers found that patients who developed anemia were more likely to achieve sustained virologic response (SVR) than those who did not, despite decreased RBV dosing following a decline in hemoglobin levels. In addition, the virologic relapse rate wasn't increased in patients who cut back on RBV dose.
These data "firmly underscore the recommendation for RBV dose reduction as the primary strategy for management of treatment-related anemia," write Dr. Mark S. Sulkowski, of Johns Hopkins University School of Medicine in Baltimore, and colleagues in the November 10th issue of Gastroenterology.
They also found that the use of erythropoiesis-stimulating agents (ESAs) minimized discontinuation of treatment in patients with early-onset anemia, leading to higher SVR rates in this subgroup.
Anemia is seen in up to 30% of treated HCV patients and often leads to RBV dose reduction and/or discontinuation of treatment, Dr. Sulkowski and colleagues note in their report.
However, because lower SVR rates have been reported in patients who cut back on RBV, "many clinicians and patients prefer to avoid this strategy and instead use ESAs (off-label) to improve anemia-related symptoms while maintaining RBV dose," the investigators note.
Nonetheless, "considerable uncertainty exists regarding the role of adjuvant ESAs during HCV treatment," they point out.
Dr. Sulkowski's team evaluated the relationship between treatment-related anemia, ESA use, and treatment outcomes in 3,023 treatment-naive patients with HCV genotype 1. All were treated for up to 48 weeks with a standard PEG-IFN/RBV regimen. ESAs were allowed for patients with hemoglobin levels less than 10 g/dL after RBV dose reduction.
Anemia occurred in 28.6% of study patients. Most of these patients lowered their RBV dose and 51.9% were given an ESA.
"Unexpectedly," the investigators say, the SVR rate was significantly higher in anemic patients than nonanemic patients (difference, +12% for anemic patients).
Moreover, SVR rates were associated with the magnitude of hemoglobin decrease. SVR rates were 43.7% in patients with an absolute hemoglobin decline greater than 3 grams per deciliter compared with 29.9% in those with a maximum decline of 3 grams per deciliter.
Patients with early-onset anemia (after 8 weeks or less of treatment) had significantly higher SVR rates with ESA use than those with later onset anemia. Those with early-onset anemia were also less apt to discontinue treatment due to adverse events (12.6% vs. 30.1%; P < 0.001).
ESAs didn't affect SVR or discontinuation rates among patients with late-onset anemia, suggesting that these patients are "not likely to benefit from adjuvant ESAs," the authors note.
The finding that RBV dose reduction wasn't associated with lower SVR rates is important, they say. "ESAs should not be used solely to avoid RBV dose reduction in anemic patients."
"Prospective, randomized controlled trials are needed to define the optimal role of adjuvant ESAs during HCV treatment regimens that include PEG-IFN/RBV," they conclude.
Gastroenterology. Posted November 10, 2010. Abstract
Source
In a large study, researchers found that patients who developed anemia were more likely to achieve sustained virologic response (SVR) than those who did not, despite decreased RBV dosing following a decline in hemoglobin levels. In addition, the virologic relapse rate wasn't increased in patients who cut back on RBV dose.
These data "firmly underscore the recommendation for RBV dose reduction as the primary strategy for management of treatment-related anemia," write Dr. Mark S. Sulkowski, of Johns Hopkins University School of Medicine in Baltimore, and colleagues in the November 10th issue of Gastroenterology.
They also found that the use of erythropoiesis-stimulating agents (ESAs) minimized discontinuation of treatment in patients with early-onset anemia, leading to higher SVR rates in this subgroup.
Anemia is seen in up to 30% of treated HCV patients and often leads to RBV dose reduction and/or discontinuation of treatment, Dr. Sulkowski and colleagues note in their report.
However, because lower SVR rates have been reported in patients who cut back on RBV, "many clinicians and patients prefer to avoid this strategy and instead use ESAs (off-label) to improve anemia-related symptoms while maintaining RBV dose," the investigators note.
Nonetheless, "considerable uncertainty exists regarding the role of adjuvant ESAs during HCV treatment," they point out.
Dr. Sulkowski's team evaluated the relationship between treatment-related anemia, ESA use, and treatment outcomes in 3,023 treatment-naive patients with HCV genotype 1. All were treated for up to 48 weeks with a standard PEG-IFN/RBV regimen. ESAs were allowed for patients with hemoglobin levels less than 10 g/dL after RBV dose reduction.
Anemia occurred in 28.6% of study patients. Most of these patients lowered their RBV dose and 51.9% were given an ESA.
"Unexpectedly," the investigators say, the SVR rate was significantly higher in anemic patients than nonanemic patients (difference, +12% for anemic patients).
Moreover, SVR rates were associated with the magnitude of hemoglobin decrease. SVR rates were 43.7% in patients with an absolute hemoglobin decline greater than 3 grams per deciliter compared with 29.9% in those with a maximum decline of 3 grams per deciliter.
Patients with early-onset anemia (after 8 weeks or less of treatment) had significantly higher SVR rates with ESA use than those with later onset anemia. Those with early-onset anemia were also less apt to discontinue treatment due to adverse events (12.6% vs. 30.1%; P < 0.001).
ESAs didn't affect SVR or discontinuation rates among patients with late-onset anemia, suggesting that these patients are "not likely to benefit from adjuvant ESAs," the authors note.
The finding that RBV dose reduction wasn't associated with lower SVR rates is important, they say. "ESAs should not be used solely to avoid RBV dose reduction in anemic patients."
"Prospective, randomized controlled trials are needed to define the optimal role of adjuvant ESAs during HCV treatment regimens that include PEG-IFN/RBV," they conclude.
Gastroenterology. Posted November 10, 2010. Abstract
Source
December 3, 2010
December 2010 B News: HBV Treatment In the News
National Strategy for the Prevention and Control of Viral Hepatitis
Dr. Howard Koh, the Assistant Secretary for Health, gave the President’s Choice Lecture at the annual meeting of the American Association for the Study of Liver Diseases (AASLD) in Boston this month, where he spoke about the U.S. administration’s response to the Institute of Medicine (IOM) report on viral hepatitis. Dr. Koh took the initiative to convene the first viral hepatitis interagency work group to look at what is being done across all Health and Human Services (HHS) agencies for this growing epidemic. A “National Strategy for the Control of Viral Hepatitis and Liver Cancer” that builds upon the IOM report is being developed by the HHS working group and is slated for publication in early 2011. Learn more »
HBV Drug Therapy Okay for Pregnant Women
Pregnant women with active hepatitis B infection can be safely and effectively treated with telbivudine (Tyzeka), researchers reported at the 2010 annual AASLD meeting. A study involving more than 80 women found that just over half of the women given telbivudine achieved a complete virologic response right before delivery compared with none of the controls, according to Calvin Pan, MD, of Mount Sinai School of Medicine in Flushing, N.Y., and colleagues. There has been a controversy over whether pregnant women with hepatitis B should be treated, mainly due to concerns over the safety of the fetus. Learn more »
HBV Reactivation and Rituximab:
A Complex Clinical Challenge
HBV reactivation is a serious and often fatal complication of rituximab-based therapy that has led to a black box warning on the package insert. Researchers report, “The importance of HBV reactivation is two-fold. First, symptomatic hepatitis flare carries a high mortality rate, which has ranged from 5 to 40% in various reports. Second, HBV reactivation, if it occurs prior to completion of chemotherapy, will likely result in substantial delays in the delivery of potentially curative chemotherapy for the underlying malignancy…such delay is detrimental to long-term cancer-specific outcome.” Read Full Article »
From Podium to Practice:
Updates in HBV Treatment
Nov. 2 – Capsule Summaries of key oral and poster presentations from the 2010 AASLD Meeting of the American Association for the Study of Liver have been selected by leading experts in the field. Learn more »
Source
Dr. Howard Koh, the Assistant Secretary for Health, gave the President’s Choice Lecture at the annual meeting of the American Association for the Study of Liver Diseases (AASLD) in Boston this month, where he spoke about the U.S. administration’s response to the Institute of Medicine (IOM) report on viral hepatitis. Dr. Koh took the initiative to convene the first viral hepatitis interagency work group to look at what is being done across all Health and Human Services (HHS) agencies for this growing epidemic. A “National Strategy for the Control of Viral Hepatitis and Liver Cancer” that builds upon the IOM report is being developed by the HHS working group and is slated for publication in early 2011. Learn more »
HBV Drug Therapy Okay for Pregnant Women
Pregnant women with active hepatitis B infection can be safely and effectively treated with telbivudine (Tyzeka), researchers reported at the 2010 annual AASLD meeting. A study involving more than 80 women found that just over half of the women given telbivudine achieved a complete virologic response right before delivery compared with none of the controls, according to Calvin Pan, MD, of Mount Sinai School of Medicine in Flushing, N.Y., and colleagues. There has been a controversy over whether pregnant women with hepatitis B should be treated, mainly due to concerns over the safety of the fetus. Learn more »
HBV Reactivation and Rituximab:
A Complex Clinical Challenge
HBV reactivation is a serious and often fatal complication of rituximab-based therapy that has led to a black box warning on the package insert. Researchers report, “The importance of HBV reactivation is two-fold. First, symptomatic hepatitis flare carries a high mortality rate, which has ranged from 5 to 40% in various reports. Second, HBV reactivation, if it occurs prior to completion of chemotherapy, will likely result in substantial delays in the delivery of potentially curative chemotherapy for the underlying malignancy…such delay is detrimental to long-term cancer-specific outcome.” Read Full Article »
From Podium to Practice:
Updates in HBV Treatment
Nov. 2 – Capsule Summaries of key oral and poster presentations from the 2010 AASLD Meeting of the American Association for the Study of Liver have been selected by leading experts in the field. Learn more »
Source
Infection and systemic inflammation, not ammonia, are associated with Grade III/IV hepatic encephalopathy, but not mortality in cirrhosis
Articles in Press
D.L. Shawcross 1‡, Y. Sharifi 1‡, J.B. Canavan 3, A.D. Yeoman 12, R.D. Abeles 12, N.J. Taylor 1, G. Auzinger 2, W. Bernal 12, J.A. Wendon 12
Received 19 April 2010; received in revised form 23 June 2010; accepted 14 July 2010. published online 01 December 2010.
Uncorrected Proof
Background & Aims
Patients with cirrhosis are prone to infection which is a frequent precipitant of hepatic encephalopathy (HE). Clinical studies have examined the importance of inflammation and infection in modulating the manifestation of symptoms of HE in acute liver failure and patients with cirrhosis and minimal/low grade HE. It would be logical to presume that this relationship persists in patients who develop severe HE in cirrhosis although this has not been examined to date.
Methods
We report the findings of a prospective audit of 100 consecutive patients with cirrhosis admitted between Jan, 2000 and March, 2008 to a liver Intensive Care Unit (ICU) where HE was the primary indication for admission (59% Grade 3; 41% Grade 4). Haematological and microbiological data were collected at ICU admission, and organ scores and outcomes were recorded.
Results
46% of patients had positive cultures taken within ±48h from admission to ICU [25% blood] and a further 22% were culture negative but had evidence of systemic inflammation (SIRS). SIRS score (p=0.03) and SOFA score (p=0.006) were significantly higher in those patients with Grade 4 HE, who were also less likely to survive (p<0.001). HE grade/coma score did not correlate with ammonia, biochemistry or MELD score. Fifty-two percent survived their ICU stay while the remainder developed progressive multiorgan failure and died; 38% survived to discharge, and 16% were transplanted.
Conclusions
These data support an association between infection/SIRS and not ammonia, in patients with cirrhosis that develop severe HE. The presence or absence of infection/SIRS did not determine survival.
Keywords: Hepatic encephalopathy, Cirrhosis, Inflammation, Infection, Outcomes
Abbreviations: APACHE, Acute Physiology and Chronic Health Evaluation, CRP, C-reactive protein, GCS, Glasgow Coma Score, HE, hepatic encephalopathy, HDU, High Dependency Unit, ICU, Intensive Care Unit, MELD, Model for End-stage Liver Disease, SIRS, Systemic Inflammatory Response Syndrome, SOFA, Sequential Organ Failure Assessment
1 Institute of Liver Studies, King’s College London School of Medicine at King’s College Hospital, Denmark Hill, London, UK
2 Liver Intensive Therapy Unit, King’s College Hospital, Denmark Hill, London, UK
3 NIHR Comprehensive Biomedical Research Centre at Guy’s & St. Thomas’s NHS Foundation Trust and King’s College London, UK
Corresponding author. Address: Institute of Liver Studies, King’s College Hospital, Denmark Hill, London SE5 9RS, UK. Tel.: +44 20 3299 2316; fax: +44 20 3299 3167.
‡ These authors contributed equally to this paper.
PII: S0168-8278(10)00838-X
doi:10.1016/j.jhep.2010.07.045
© 2010 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.
Source
D.L. Shawcross 1‡, Y. Sharifi 1‡, J.B. Canavan 3, A.D. Yeoman 12, R.D. Abeles 12, N.J. Taylor 1, G. Auzinger 2, W. Bernal 12, J.A. Wendon 12
Received 19 April 2010; received in revised form 23 June 2010; accepted 14 July 2010. published online 01 December 2010.
Uncorrected Proof
Background & Aims
Patients with cirrhosis are prone to infection which is a frequent precipitant of hepatic encephalopathy (HE). Clinical studies have examined the importance of inflammation and infection in modulating the manifestation of symptoms of HE in acute liver failure and patients with cirrhosis and minimal/low grade HE. It would be logical to presume that this relationship persists in patients who develop severe HE in cirrhosis although this has not been examined to date.
Methods
We report the findings of a prospective audit of 100 consecutive patients with cirrhosis admitted between Jan, 2000 and March, 2008 to a liver Intensive Care Unit (ICU) where HE was the primary indication for admission (59% Grade 3; 41% Grade 4). Haematological and microbiological data were collected at ICU admission, and organ scores and outcomes were recorded.
Results
46% of patients had positive cultures taken within ±48h from admission to ICU [25% blood] and a further 22% were culture negative but had evidence of systemic inflammation (SIRS). SIRS score (p=0.03) and SOFA score (p=0.006) were significantly higher in those patients with Grade 4 HE, who were also less likely to survive (p<0.001). HE grade/coma score did not correlate with ammonia, biochemistry or MELD score. Fifty-two percent survived their ICU stay while the remainder developed progressive multiorgan failure and died; 38% survived to discharge, and 16% were transplanted.
Conclusions
These data support an association between infection/SIRS and not ammonia, in patients with cirrhosis that develop severe HE. The presence or absence of infection/SIRS did not determine survival.
Keywords: Hepatic encephalopathy, Cirrhosis, Inflammation, Infection, Outcomes
Abbreviations: APACHE, Acute Physiology and Chronic Health Evaluation, CRP, C-reactive protein, GCS, Glasgow Coma Score, HE, hepatic encephalopathy, HDU, High Dependency Unit, ICU, Intensive Care Unit, MELD, Model for End-stage Liver Disease, SIRS, Systemic Inflammatory Response Syndrome, SOFA, Sequential Organ Failure Assessment
1 Institute of Liver Studies, King’s College London School of Medicine at King’s College Hospital, Denmark Hill, London, UK
2 Liver Intensive Therapy Unit, King’s College Hospital, Denmark Hill, London, UK
3 NIHR Comprehensive Biomedical Research Centre at Guy’s & St. Thomas’s NHS Foundation Trust and King’s College London, UK
Corresponding author. Address: Institute of Liver Studies, King’s College Hospital, Denmark Hill, London SE5 9RS, UK. Tel.: +44 20 3299 2316; fax: +44 20 3299 3167.
‡ These authors contributed equally to this paper.
PII: S0168-8278(10)00838-X
doi:10.1016/j.jhep.2010.07.045
© 2010 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.
Source
Arizona Cuts Financing for Transplant Patients
By MARC LACEY
Published: December 2, 2010
PHOENIX — Even physicians with decades of experience telling patients that their lives are nearing an end are having difficulty discussing a potentially fatal condition that has arisen in Arizona: Death by budget cut.
Effective at the beginning of October, Arizona stopped financing certain transplant operations under the state’s version of Medicaid. Many doctors say the decision amounts to a death sentence for some low-income patients, who have little chance of survival without transplants and lack the hundreds of thousands of dollars needed to pay for them.
“The most difficult discussions are those that involve patients who had been on the donor list for a year or more and now we have to tell them they’re not on the list anymore,” said Dr. Rainer Gruessner, a transplant specialist at the University of Arizona College of Medicine. “The frustration is tremendous. It’s more than frustration.”
Organ transplants are already the subject of a web of regulations, which do not guarantee that everyone in need of a life-saving organ will receive one. But Arizona’s transplant specialists are alarmed that patients who were in line to receive transplants one day were, after the state’s budget cuts to its Medicaid program, ruled ineligible the next — unless they raised the money themselves.
Francisco Felix, 32, a father of four who has hepatitis C and is in need of a liver, received news a few weeks ago that a family friend was dying and wanted to donate her liver to him. But the budget cuts meant he no longer qualified for a state-financed transplant.
He was prepared anyway at Banner Good Samaritan Medical Center as his relatives scrambled to raise the needed $200,000. When the money did not come through, the liver went to someone else on the transplant list.
“I know times are tight and cuts are needed, but you can’t cut human lives,” said Mr. Felix’s wife, Flor. “You just can’t do that.”
Such high drama is unfolding regularly here as more and more of the roughly 100 people affected by the cuts are becoming known: the father of six who died before receiving a bone marrow transplant, the plumber in need of a new heart and the high school basketball coach who struggles to breathe during games at high altitudes as she awaits a lung transplant.
“I appreciate the need for budget restraints,” said Dr. Andrew M. Yeager, a University of Arizona professor who is director of the Blood and Marrow Transplantation Program at the Arizona Cancer Center. “But when one looks at a potentially lifesaving treatment, admittedly expensive, and we have data to support efficacy, cuts like this are shortsighted and sad.”
State Medicaid officials said they recommended discontinuing some transplants only after assessing the success rates for previous patients. Among the discontinued procedures are lung transplants, liver transplants for hepatitis C patients and some bone marrow and pancreas transplants, which altogether would save the state about $4.5 million a year.
“As an agency, we understand there have been difficult cuts and there will have to be more difficult cuts looking forward,” said Jennifer Carusetta, chief legislative liaison at the state Medicaid agency.
The issue has led to a fierce political battle, with Democrats condemning the reductions as “Brewercare,” after Gov. Jan Brewer.
“We made it very clear at the time of the vote that this was a death sentence,” said State Senator Leah Landrum Taylor, a Democrat. “This is not a luxury item. We’re not talking about cosmetic surgery.”
The Republican governor has in turn blamed “Obamacare,” meaning the federal health care overhaul, for the transplant cuts even though the Arizona vote came in March, before President Obama signed that bill into law.
But a top Republican, State Representative John Kavanagh, has already pledged to reconsider at least some of the state’s cuts for transplants when the Legislature reconvenes in January. Mr. Kavanagh, chairman of the Appropriations Committee, said he does not believe lawmakers had the full picture of the effect of the cuts on patients when they voted.
“It’s difficult to be linked to a situation where people’s lives are jeopardized and turned upside down,” he said in an interview. “Thankfully no one has died as a result of this, and I believe we have time to rectify this.”
Across the country, states have restricted benefits to their Medicaid programs, according to a 50-state survey published in September by the Kaiser Commission on Medicaid and the Uninsured. But none have gone as far as Arizona in eliminating some transplants, which are considered optional services under federal law.
Before the Legislature acted, Arizona’s Medicaid agency had provided an analysis to lawmakers of the transplants that were cut, which many health experts now say was seriously flawed. For instance, the state said that 13 of 14 patients under the state’s health system who received bone marrow transplants from nonrelatives over a two-year period died within six months.
But outside specialists said the success rates were considerably higher, particularly for leukemia patients in their first remission.
“Something needs to be done,” said Dr. Emmanuel Katsanis, a bone marrow transplant expert at the University of Arizona. “There’s no doubt that people aren’t going to make it because of this decision. What do you tell someone? You need a transplant but you have to raise the money?”
Just before the Oct. 1 deadline, Mark Price, a father of six who was fighting leukemia, learned he needed a bone marrow transplant. But his doctor, Jeffrey R. Schriber, found donor matches for his transplant the very day the new rules went into effect, and Mr. Price no longer qualified for coverage by the Arizona Health Care Cost Containment System, the formal name for the state’s Medicaid program.
What happened next was at once inspirational and heart-rending.
Out of the blue, an anonymous financial donor quickly stepped forward and agreed to cover the hundreds of thousands of dollars needed for Mr. Price’s surgery. But Mr. Price died last weekend, after his cancer returned before the operation could be done. He was buried on Thursday, next to his grandfather.
“It’s not correct to say that he died as a result of the cuts,” said Dr. Schriber, who is active in lobbying for the financing to be restored. “Did it prey on his mind? Did it make his last days more difficult? No doubt.”
Elsewhere, the fund-raising is already under way.
Mr. Felix and others are now trying to raise enough for new organs through NTAF, a nonprofit organization based in Pennsylvania formerly known as the National Transplant Assistance Fund that helps transplant patients pay for their medical costs. National coverage of their plight has already led to more than $100,000 in donations for some of the patients affected by the budget cuts. The Felix family is also planning a yard sale this weekend so he does not lose the chance to get another liver.
There has been a flurry of lobbying to persuade the state to reverse the decision. Dr. Gruessner said he and others met with state health officials recently to propose other cuts associated with transplants, like eliminating tests typically conducted before surgery.
If the Legislature does decide to reconsider the cuts, one of the affected people, a plumber and father of three named Randy Shepherd, 36, who has an ailing heart and needs a transplant, plans to attend the debate.
“I’m trying not to take it personally,” he said of being cut out of the program. “None of the politicians had heard of me when they made their decision. They didn’t say, ‘Let’s kill this guy.’ ”
Source
Published: December 2, 2010
PHOENIX — Even physicians with decades of experience telling patients that their lives are nearing an end are having difficulty discussing a potentially fatal condition that has arisen in Arizona: Death by budget cut.
Effective at the beginning of October, Arizona stopped financing certain transplant operations under the state’s version of Medicaid. Many doctors say the decision amounts to a death sentence for some low-income patients, who have little chance of survival without transplants and lack the hundreds of thousands of dollars needed to pay for them.
“The most difficult discussions are those that involve patients who had been on the donor list for a year or more and now we have to tell them they’re not on the list anymore,” said Dr. Rainer Gruessner, a transplant specialist at the University of Arizona College of Medicine. “The frustration is tremendous. It’s more than frustration.”
Organ transplants are already the subject of a web of regulations, which do not guarantee that everyone in need of a life-saving organ will receive one. But Arizona’s transplant specialists are alarmed that patients who were in line to receive transplants one day were, after the state’s budget cuts to its Medicaid program, ruled ineligible the next — unless they raised the money themselves.
Francisco Felix, 32, a father of four who has hepatitis C and is in need of a liver, received news a few weeks ago that a family friend was dying and wanted to donate her liver to him. But the budget cuts meant he no longer qualified for a state-financed transplant.
He was prepared anyway at Banner Good Samaritan Medical Center as his relatives scrambled to raise the needed $200,000. When the money did not come through, the liver went to someone else on the transplant list.
“I know times are tight and cuts are needed, but you can’t cut human lives,” said Mr. Felix’s wife, Flor. “You just can’t do that.”
Such high drama is unfolding regularly here as more and more of the roughly 100 people affected by the cuts are becoming known: the father of six who died before receiving a bone marrow transplant, the plumber in need of a new heart and the high school basketball coach who struggles to breathe during games at high altitudes as she awaits a lung transplant.
“I appreciate the need for budget restraints,” said Dr. Andrew M. Yeager, a University of Arizona professor who is director of the Blood and Marrow Transplantation Program at the Arizona Cancer Center. “But when one looks at a potentially lifesaving treatment, admittedly expensive, and we have data to support efficacy, cuts like this are shortsighted and sad.”
State Medicaid officials said they recommended discontinuing some transplants only after assessing the success rates for previous patients. Among the discontinued procedures are lung transplants, liver transplants for hepatitis C patients and some bone marrow and pancreas transplants, which altogether would save the state about $4.5 million a year.
“As an agency, we understand there have been difficult cuts and there will have to be more difficult cuts looking forward,” said Jennifer Carusetta, chief legislative liaison at the state Medicaid agency.
The issue has led to a fierce political battle, with Democrats condemning the reductions as “Brewercare,” after Gov. Jan Brewer.
“We made it very clear at the time of the vote that this was a death sentence,” said State Senator Leah Landrum Taylor, a Democrat. “This is not a luxury item. We’re not talking about cosmetic surgery.”
The Republican governor has in turn blamed “Obamacare,” meaning the federal health care overhaul, for the transplant cuts even though the Arizona vote came in March, before President Obama signed that bill into law.
But a top Republican, State Representative John Kavanagh, has already pledged to reconsider at least some of the state’s cuts for transplants when the Legislature reconvenes in January. Mr. Kavanagh, chairman of the Appropriations Committee, said he does not believe lawmakers had the full picture of the effect of the cuts on patients when they voted.
“It’s difficult to be linked to a situation where people’s lives are jeopardized and turned upside down,” he said in an interview. “Thankfully no one has died as a result of this, and I believe we have time to rectify this.”
Across the country, states have restricted benefits to their Medicaid programs, according to a 50-state survey published in September by the Kaiser Commission on Medicaid and the Uninsured. But none have gone as far as Arizona in eliminating some transplants, which are considered optional services under federal law.
Before the Legislature acted, Arizona’s Medicaid agency had provided an analysis to lawmakers of the transplants that were cut, which many health experts now say was seriously flawed. For instance, the state said that 13 of 14 patients under the state’s health system who received bone marrow transplants from nonrelatives over a two-year period died within six months.
But outside specialists said the success rates were considerably higher, particularly for leukemia patients in their first remission.
“Something needs to be done,” said Dr. Emmanuel Katsanis, a bone marrow transplant expert at the University of Arizona. “There’s no doubt that people aren’t going to make it because of this decision. What do you tell someone? You need a transplant but you have to raise the money?”
Just before the Oct. 1 deadline, Mark Price, a father of six who was fighting leukemia, learned he needed a bone marrow transplant. But his doctor, Jeffrey R. Schriber, found donor matches for his transplant the very day the new rules went into effect, and Mr. Price no longer qualified for coverage by the Arizona Health Care Cost Containment System, the formal name for the state’s Medicaid program.
What happened next was at once inspirational and heart-rending.
Out of the blue, an anonymous financial donor quickly stepped forward and agreed to cover the hundreds of thousands of dollars needed for Mr. Price’s surgery. But Mr. Price died last weekend, after his cancer returned before the operation could be done. He was buried on Thursday, next to his grandfather.
“It’s not correct to say that he died as a result of the cuts,” said Dr. Schriber, who is active in lobbying for the financing to be restored. “Did it prey on his mind? Did it make his last days more difficult? No doubt.”
Elsewhere, the fund-raising is already under way.
Mr. Felix and others are now trying to raise enough for new organs through NTAF, a nonprofit organization based in Pennsylvania formerly known as the National Transplant Assistance Fund that helps transplant patients pay for their medical costs. National coverage of their plight has already led to more than $100,000 in donations for some of the patients affected by the budget cuts. The Felix family is also planning a yard sale this weekend so he does not lose the chance to get another liver.
There has been a flurry of lobbying to persuade the state to reverse the decision. Dr. Gruessner said he and others met with state health officials recently to propose other cuts associated with transplants, like eliminating tests typically conducted before surgery.
If the Legislature does decide to reconsider the cuts, one of the affected people, a plumber and father of three named Randy Shepherd, 36, who has an ailing heart and needs a transplant, plans to attend the debate.
“I’m trying not to take it personally,” he said of being cut out of the program. “None of the politicians had heard of me when they made their decision. They didn’t say, ‘Let’s kill this guy.’ ”
Source
Manifestations of Chronic Hepatitis C Virus Infection Beyond the Liver
Clinical Gastroenterology and Hepatology
Volume 8, Issue 12 , Pages 1017-1029, December 2010
Ira M. Jacobson , Patrice Cacoub, Luigino Dal Maso, Stephen A. Harrison, Zobair M. Younossi
Abstract
In addition to its effects in the liver, chronic hepatitis C virus (HCV) infection can have serious consequences for other organ systems. Extrahepatic manifestations include mixed cryoglobulinemia (MC) vasculitis, lymphoproliferative disorders, renal disease, insulin resistance, type 2 diabetes, sicca syndrome, rheumatoid arthritis–like polyarthritis, and autoantibody production; reductions in quality of life involve fatigue, depression, and cognitive impairment. MC vasculitis, certain types of lymphoma, insulin resistance, and cognitive function appear to respond to anti-HCV therapy. However, treatments for HCV and other biopsychosocial factors can reduce quality of life and complicate management. HCV treatment has a high overall cost that increases when extrahepatic manifestations are considered. HCV appears to have a role in the pathogenesis of MC vasculitis, certain types of lymphoma, and insulin resistance. Clinicians who treat patients with HCV infections should be aware of potential extrahepatic manifestations and how these can impact and alter management of their patients.
Keywords: Hepatitis C Virus, Burden of Disease, Extrahepatic Comorbidities, Health-Related Quality of Life, Epidemiology
Source
Volume 8, Issue 12 , Pages 1017-1029, December 2010
Ira M. Jacobson , Patrice Cacoub, Luigino Dal Maso, Stephen A. Harrison, Zobair M. Younossi
Abstract
In addition to its effects in the liver, chronic hepatitis C virus (HCV) infection can have serious consequences for other organ systems. Extrahepatic manifestations include mixed cryoglobulinemia (MC) vasculitis, lymphoproliferative disorders, renal disease, insulin resistance, type 2 diabetes, sicca syndrome, rheumatoid arthritis–like polyarthritis, and autoantibody production; reductions in quality of life involve fatigue, depression, and cognitive impairment. MC vasculitis, certain types of lymphoma, insulin resistance, and cognitive function appear to respond to anti-HCV therapy. However, treatments for HCV and other biopsychosocial factors can reduce quality of life and complicate management. HCV treatment has a high overall cost that increases when extrahepatic manifestations are considered. HCV appears to have a role in the pathogenesis of MC vasculitis, certain types of lymphoma, and insulin resistance. Clinicians who treat patients with HCV infections should be aware of potential extrahepatic manifestations and how these can impact and alter management of their patients.
Keywords: Hepatitis C Virus, Burden of Disease, Extrahepatic Comorbidities, Health-Related Quality of Life, Epidemiology
Source
Vitamin D supplementation improves response to antiviral treatment for recurrent hepatitis C
Transplant International
Volume 24, Issue 1, pages 43–50, January 2011
DOI: 10.1111/j.1432-2277.2010.01141.x
Davide Bitetto 1, Carlo Fabris 1, Ezio Fornasiere 1, Corrado Pipan 2, Elisa Fumolo 1, Annarosa Cussigh 1, Sara Bignulin 1, Sara Cmet 1, Elisabetta Fontanini 1, Edmondo Falleti 1, Romina Martinella 2, Mario Pirisi 3,4, Pierluigi Toniutto 1
Author Information
1 Medical Liver Transplantation Unit, Internal Medicine, University of Udine, Udine, Italy
2 Hygiene and Epidemiology, University of Udine, Udine, Italy
3 Department of Clinical and Experimental Medicine, University of Eastern Piedmont “A. Avogadro”, Novara, Italy
4 Interdisciplinary Research Center of Autoimmune Diseases, University of Eastern Piedmont “A. Avogadro”, Novara, Italy
*Correspondence: Pierluigi Toniutto MD, DPMSC, Internal Medicine, Medical Liver Transplantation Unit, University of Udine, 33100 Udine, Italy. Tel.: +390432559801; fax: +39043242097; e-mail: pierluigi.toniutto@uniud.it
Abstract
Keywords: interferon; liver transplantation; recurrent hepatitis C; vitamin D
Summary
In immune-competent patients, higher vitamin D levels predicted sustained viral response (SVR) following interferon (INF) and ribavirin therapy for chronic hepatitis C. This study aimed to verify the influence of vitamin D serum levels and/or vitamin D supplementation in predicting SVR rates for recurrent hepatitis C (RHC). Forty-two consecutive patients were treated for RHC with combination therapy with INF-α and ribavirin for 48 weeks. Vitamin D serum levels were measured in all patients before antiviral therapy. In 15 patients oral vitamin D3 supplementation was administered to avoid further bone loss. SVR was observed in 13 patients; it was achieved in 1/10 severely vitamin D deficient (≤10 ng/ml) patients, in 6/20 deficient (>10 and ≤20 ng/ml) and in 6/12 with near normal (>20 ng/ml) 25-OH vitamin D serum levels (P < 0.05). Cholecalciferol supplementation, in the presence of a normal or near normal baseline vitamin D concentration, (improvement of chi-square P < 0.05, odds ratio 2.22) and possessing a genotype other than 1 (improvement of chi-square P < 0.05, odds ratio 3.383) were the only variables independently associated to SVR. In conclusion, vitamin D deficiency predicts an unfavourable response to antiviral treatment of RHC. Vitamin D supplementation improves the probability of achieving a SVR following antiviral treatment.
Source
Volume 24, Issue 1, pages 43–50, January 2011
DOI: 10.1111/j.1432-2277.2010.01141.x
Davide Bitetto 1, Carlo Fabris 1, Ezio Fornasiere 1, Corrado Pipan 2, Elisa Fumolo 1, Annarosa Cussigh 1, Sara Bignulin 1, Sara Cmet 1, Elisabetta Fontanini 1, Edmondo Falleti 1, Romina Martinella 2, Mario Pirisi 3,4, Pierluigi Toniutto 1
Author Information
1 Medical Liver Transplantation Unit, Internal Medicine, University of Udine, Udine, Italy
2 Hygiene and Epidemiology, University of Udine, Udine, Italy
3 Department of Clinical and Experimental Medicine, University of Eastern Piedmont “A. Avogadro”, Novara, Italy
4 Interdisciplinary Research Center of Autoimmune Diseases, University of Eastern Piedmont “A. Avogadro”, Novara, Italy
*Correspondence: Pierluigi Toniutto MD, DPMSC, Internal Medicine, Medical Liver Transplantation Unit, University of Udine, 33100 Udine, Italy. Tel.: +390432559801; fax: +39043242097; e-mail: pierluigi.toniutto@uniud.it
Abstract
Keywords: interferon; liver transplantation; recurrent hepatitis C; vitamin D
Summary
In immune-competent patients, higher vitamin D levels predicted sustained viral response (SVR) following interferon (INF) and ribavirin therapy for chronic hepatitis C. This study aimed to verify the influence of vitamin D serum levels and/or vitamin D supplementation in predicting SVR rates for recurrent hepatitis C (RHC). Forty-two consecutive patients were treated for RHC with combination therapy with INF-α and ribavirin for 48 weeks. Vitamin D serum levels were measured in all patients before antiviral therapy. In 15 patients oral vitamin D3 supplementation was administered to avoid further bone loss. SVR was observed in 13 patients; it was achieved in 1/10 severely vitamin D deficient (≤10 ng/ml) patients, in 6/20 deficient (>10 and ≤20 ng/ml) and in 6/12 with near normal (>20 ng/ml) 25-OH vitamin D serum levels (P < 0.05). Cholecalciferol supplementation, in the presence of a normal or near normal baseline vitamin D concentration, (improvement of chi-square P < 0.05, odds ratio 2.22) and possessing a genotype other than 1 (improvement of chi-square P < 0.05, odds ratio 3.383) were the only variables independently associated to SVR. In conclusion, vitamin D deficiency predicts an unfavourable response to antiviral treatment of RHC. Vitamin D supplementation improves the probability of achieving a SVR following antiviral treatment.
Source
Approval of rapid INSTI[TM] HIV-1 Antibody Test
On November 29, 2010, the Food and Drug Administration (FDA) announced the approval of the INSTI™ HIV-1 Antibody Test, a new, single use rapid test for the detection of antibodies to Human Immunodeficiency Virus Type 1 (HIV-1) in human venipuncture whole blood, fingerstick blood, or plasma specimens. The newly approved test provides results in as little as 60 seconds, in contrast to the six previously approved rapid HIV tests, which typically deliver results in about 10 - 20 minutes.
Rapid HIV tests allow people to learn their HIV status in a single visit to a testing site, instead of returning days later for results, dramatically increasing the number of people who ultimately learn their serostatus after taking an HIV test.
Rapid testing also helps increase access to HIV testing because testing can be performed outside of the traditional laboratory setting. Individuals who undergo testing can be counseled immediately concerning their HIV status and, if they are positive, given the opportunity to enter medical care.
The INSTI™ HIV-1 Antibody Test can be used in clinical laboratories, in public health laboratories and in point-of-care settings. The test is classified as Moderate Complexity under CLIA (Clinical Laboratory Improvements Amendments).
It is highly sensitive [The overall sensitivity for the different sample types: 99.8% (95% CI = 99.3% - 99.9%) in fingerstick whole blood, 99.9% (95% CI = 99.5% - 100%) in venipuncture whole blood, 99.9% (95% CI = 99.5% - 100%) in plasma] and specific [The overall specificity for the different samples types: 99.5% (95% CI = 99.0% - 99.8) in fingerstick whole blood, 100% (95% CI = 99.7% - 100%) in venipuncture whole blood, 100% (95% CI = 99.7% - 100%) in plasma] for the detection of antibodies to HIV-1.
The assay is not intended to be used for screening of blood donors.
The INSTI™ HIV-1 Antibody Test is manufactured by bioLytical Laboratories Inc., Richmond, BC, Canada.
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration
Source
Rapid HIV tests allow people to learn their HIV status in a single visit to a testing site, instead of returning days later for results, dramatically increasing the number of people who ultimately learn their serostatus after taking an HIV test.
Rapid testing also helps increase access to HIV testing because testing can be performed outside of the traditional laboratory setting. Individuals who undergo testing can be counseled immediately concerning their HIV status and, if they are positive, given the opportunity to enter medical care.
The INSTI™ HIV-1 Antibody Test can be used in clinical laboratories, in public health laboratories and in point-of-care settings. The test is classified as Moderate Complexity under CLIA (Clinical Laboratory Improvements Amendments).
It is highly sensitive [The overall sensitivity for the different sample types: 99.8% (95% CI = 99.3% - 99.9%) in fingerstick whole blood, 99.9% (95% CI = 99.5% - 100%) in venipuncture whole blood, 99.9% (95% CI = 99.5% - 100%) in plasma] and specific [The overall specificity for the different samples types: 99.5% (95% CI = 99.0% - 99.8) in fingerstick whole blood, 100% (95% CI = 99.7% - 100%) in venipuncture whole blood, 100% (95% CI = 99.7% - 100%) in plasma] for the detection of antibodies to HIV-1.
The assay is not intended to be used for screening of blood donors.
The INSTI™ HIV-1 Antibody Test is manufactured by bioLytical Laboratories Inc., Richmond, BC, Canada.
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration
Source
December 2, 2010
Peregrine Pharmaceuticals initiates phase I/II trial for HCC
Dec 02, 2010 (Datamonitor via COMTEX) --
Peregrine Pharmaceuticals, Inc., a clinical-stage biopharmaceutical company engaged in development of monoclonal antibody-based drugs, has initiated an investigator-sponsored trial, or IST, for patients with advanced hepatocellular carcinoma, or HCC, or liver cancer.
This phase I/II trial will treat patients with Peregrine's investigational monoclonal antibody bavituximab in combination with sorafenib.
Currently, Peregrine's bavituximab is being evaluated in combination with chemotherapy in multiple phase II trials in non-small cell lung cancer and advanced breast cancer, as well as a phase Ib trial for hepatitis C virus (HCV) and HIV coinfection.
"In prior studies, bavituximab has demonstrated broad therapeutic potential in multiple oncology indications," said Marvin R. Garovoy, M.D., head of clinical science at Peregrine Pharmaceuticals. "Our IST program is designed to provide valuable clinical data on bavituximab's potential use in different therapeutic combinations and indications. We also expect to further clarify details of bavituximab's multiple mechanisms of action, and to identify specific biomarkers that could ultimately help to measure and predict bavituximab's potential anti-tumor and immunostimulatory effects. We look forward to collaborating with Dr Yopp and his team, as well as other investigators who have applied for our program."
Source
Peregrine Pharmaceuticals, Inc., a clinical-stage biopharmaceutical company engaged in development of monoclonal antibody-based drugs, has initiated an investigator-sponsored trial, or IST, for patients with advanced hepatocellular carcinoma, or HCC, or liver cancer.
This phase I/II trial will treat patients with Peregrine's investigational monoclonal antibody bavituximab in combination with sorafenib.
Currently, Peregrine's bavituximab is being evaluated in combination with chemotherapy in multiple phase II trials in non-small cell lung cancer and advanced breast cancer, as well as a phase Ib trial for hepatitis C virus (HCV) and HIV coinfection.
"In prior studies, bavituximab has demonstrated broad therapeutic potential in multiple oncology indications," said Marvin R. Garovoy, M.D., head of clinical science at Peregrine Pharmaceuticals. "Our IST program is designed to provide valuable clinical data on bavituximab's potential use in different therapeutic combinations and indications. We also expect to further clarify details of bavituximab's multiple mechanisms of action, and to identify specific biomarkers that could ultimately help to measure and predict bavituximab's potential anti-tumor and immunostimulatory effects. We look forward to collaborating with Dr Yopp and his team, as well as other investigators who have applied for our program."
Source
The Journey East
Tuesday, 30 November 2010 13:10 Sean Foley
Santa Cruz local walks cross-country to raise awareness for Hepatitis C
In the age of freeways and airplanes, transportation is fast and efficient, if not a little dehumanizing. We live in a time in which most people hop in their cars to run even the smallest errand. But this winter, one Santa Cruz resident is ditching his car and hitting the road for a transcontinental trip—on foot.
Meet Joseph Melsha. On Friday, Nov. 26, the Santa Cruz native embarked on a journey that will take him through the United States, with nothing more than a bag stocked with basic amenities (a tent, flashlight, and a small camp stove) on his back and a sturdy pair of walking shoes on his feet. He has plotted a course that will take him to his final destination in Boston, Mass.
Melsha isn’t walking across the United States merely for fun; he’s putting his feet to use to raise awareness throughout the country about a harmful disease, Hepatitis C. Melsha lost his mother to Hepatitis C in 2005. His sister, who lives in Boston, currently lives with the condition, and Melsha’s venture through the country will ultimately lead him to her.
“Walking is the easy part,” Melsha says. “I’ve been walking since I was a year old.” However, walking across the country at the onset of winter is another story. The brutal Midwestern winter prevented Melsha from taking a linear route across the country. Instead, he will tread southward towards Santa Monica and then follow Route 66 through the southwest. He plans to eventually end up in Jacksonville, Fla. before making the final trek up north to Boston.
Melsha decided to walk to Boston to raise awareness on a whim. “In this economy, it’s hard to find work,” he says. “I just felt like I wanted to do something positive with my time … and then I decided I need to see my sister … I just decided, ‘I’m walking to Boston! See everyone in a few months!’”
He decided to make his journey to see his sister an effort that would galvanize the public and spread knowledge about Hepatitis C. Hepatitis C is a disease caused from the Hepatitis C virus. It infects the liver and can lead to cirrhosis, liver cancer, and other permanent or long-term liver damage, according to WebMD. The virus gets spread through contact with infected blood. The Center for Disease Control (CDC) reports that approximately 3.2 million people in the United States live with chronic Hepatitis C.
Spreading awareness by walking will be more effective than by travelling through the country by other means because “it takes longer, and it’s a big deal,” says Melsha. “Everybody wonders, ‘So what, Hep. C?’ and then ‘What’s Hep. C?’ and I’ve already raised a tremendous amount of awareness and I haven’t even started walking yet.”
Just days before he set off, Melsha told Good Times that he was encouraged by the attention he had already received from fellow Santa Cruzans. “Everywhere I go people are like, ‘Oh, hey you’re Joe Melsha.’ These are people I’ve never seen before, at places like the grocery store,” he says.
In addition, Melsha has received a lot of electronic support. “Every morning I have over 200 emails with people sharing their stories,” he says. “I wake up crying basically. They’re saying such nice things. Already this has exceeded my expectations.” His visibility can in part be measured through the popularity of his Facebook page, which now receives a barrage of friend requests daily.
As he walks, Melsha will periodically update his fans and followers with photo and video updates on his Facebook page as well as on his personal website, joemelsha.com. These updates will occur whenever he has access to a computer. (“It’s all very informal,” he says.) He plans on walking 10 to 12 hours a day for as long as it takes for him to reach Boston. Although he hasn’t been training at a gym (“I’ve been training by eating Twinkies and staying on my feet … trying to gain a little weight before the journey,” he quips), Melsha feels that he could make it to Boston in as little as 100 days. He estimates the walk will actually take him about six months to complete.
As he walks and educates those he meets, Melsha hopes to inspire others to find a cause they are passionate about. He says, “I want to show people [that] you can do something with your life … You don’t have to be anyone, I’m just Joe Melsha, and I’m just walking.”
Source
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