March 26, 2014

The Promise of New HCV Therapies

HCV Next, January/February 2014

Your guide to the age after interferon

NewDrug

The future of treatment for hepatitis C virus infection is exciting. Many new drugs and combination therapies are moving rapidly through clinical trials and are becoming part of the conversation for FDA approval. The most recently approved tools at the disposal of clinicians are sofosbuvir and simeprevir, oral therapies that are associated with high cure rates.

The fast pace of development begs the question of whether an interferon-free future is near. Interferon has been the backbone of HCV treatment since it was approved by the FDA in 1991 for the treatment of HCV. In 1998, the addition of ribavirin to interferon was approved. Since the approval of pegylated interferon in 2001, the gold standard of treatment has been pegylated interferon with ribavirin with or without a protease inhibitor. However, the downsides associated with interferon, including adverse effects, need for careful monitoring and the fact that some patients are ineligible for treatment, and have left many desiring an interferon-free regimen.

Yet, interferon therapy is not quite a thing of the past. The approach figures into several recommended treatment options featured on HCVguidelines.org, the website recently launched by the American Association for the Study of Liver Diseases and Infectious Diseases Society of America, in collaboration with the International Antiviral Society-USA, which will serve as the clinical guidelines for HCV treatment in the United States (See Feature). However, a range of non-nucleoside polymerase inhibitors, nucleoside/nucleotide polymerase inhibitors, NS5A inhibitors, protease inhibitors and combinations thereof have demonstrated such overwhelmingly encouraging cure rates across genotypes in clinical trials that many believe the days of interferon are numbered.

The FDA has acted accordingly and provided accelerated 6-month approval status for several combination therapies. The speed with which new therapies are evolving has raised some eyebrows in the clinical community, but Donald M. Jensen, MD, said the development process is working exactly as it should.

“The duration of therapy is shorter with many of these drugs,” said Jensen, who is professor of medicine and director of the Center for Liver Diseases at University of Chicago Medical Center. Most combinations are being studied for 8 to 12 weeks of therapy and 12 weeks of follow-up.

“This has made the development of agents much quicker than with pegylated interferon and ribavirin-based therapies,” Jensen, a co-chair on the HCVguidelines.org panel, said. “The time factor has allowed for big breakthroughs and has opened the door for a number of combinations to be still in the game — not on the sideline.”

Andrew J. Muir, MD, MPH, associate professor of medicine and clinical director of hepatology at Duke University, put the issue in clinical terms: “The concern is not the pace of the FDA-approval process. The concern is that patients are dying of cirrhosis and liver cancer. We now have the tools to stop this disease and end pain and suffering.”

HCV Next spoke with several experts about the current drug pipeline. Their insights may help clinicians who treat this disease prepare for 2014 and beyond.

Continue reading full article here …..

The HCV Revolution Did Not Happen Overnight

ACS Medical Chemistry Letters

Ann D. Kwong *
InnovaTID, Inc., 125 Cambridge Park Drive, Cambridge,
Massachusetts 02140, United States

ACS Med. Chem. Lett., 2014, 5 (3), pp 214–220
DOI: 10.1021/ml500070q
Publication Date (Web): February 27, 2014
Copyright © 2014 American Chemical Society

*E-mail: ann.kwong@innovatid.org. Phone: 617-501-3453.

Abstract

The progress in HCV therapy in the last three years is similar to the progress that took HIV therapy 14 years. We are at the brink of approval for an all-oral drug combination that is dosed once daily as a single pill, has >95% efficacy, and is well tolerated. This article summarizes the path to this success and the challenges still ahead.

Looking back at the last 20 years in HCV drug discovery, I am struck by how fast the progress has been in recent years, and how slow it was in the early years. This viewpoint will attempt to identify some of the factors that contributed to both effects, in the hope that the knowledge will inform and accelerate future drug discovery.

HCV Revolution

The past decade was an exciting time in the world of hepatitis C virus (HCV) drug discovery. By 2011, over 50 companies worked on HCV, and in 2013, more than a dozen were conducting phase 2 and phase 3 clinical trials.(1) The past few years saw rapid progression toward “the Holy Grail” of HCV: an all-oral, highly tolerable therapy with a >95% cure rate for all chronic HCV infections. The FDA approved two first-generation HCV protease inhibitors in 2011, then a second-generation HCV protease inhibitor and a HCV polymerase nucleotide inhibitor in 2013. In addition, excellent phase 3 data has been reported for several all-oral drug combinations, which may launch in 2014 (Figure 1). Treatment success rates improved from 40% in 2001 to 79% in 2011 and 89% in 2013, with multiple phase 3 trials with oral combinations reporting efficacy rates above 95%. Remarkably, increased efficacy of the new regimens came without increased toxicity or less tolerability.

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Figure 1. Nonhead-to-head comparison of efficacy vs duration of HCV treatment regimens for different HCV genotypes as a function of the year of regulatory approval. The data reported are derived from multiple sources and different clinical trials and are shown side-by-side for pedagogical purposes and should not be construed to be definitive numbers. Efficacy (blue columns): the % sustained viral response (SVR), i.e., the % cure rate. A patient is said the be “cured” or have a “SVR” if their plasma HCV RNA levels become undetectable during treatment and remain undetectable for 24 weeks after the end of treatment. Duration (yellow columns): the total length of time a patient is on antiviral therapy, not just the length of time a patient is receiving a direct acting antiviral (DAA) drug. All the treatment durations shown in the graph were 12, 24, or 48 weeks. Geno, genotype; IFN, interferon; PR, pegylated interferon alfa 2a/b and ribavirin; RBV, ribavirin; DAA, direct acting antiviral.

Unmet Medical Need

HCV is a blood borne pathogen that chronically infects 170 million people. Thorough screening of blood supplies has significantly reduced new infections. Globally, the incidence of disease and the market for HCV drugs are inversely related. The Western Pacific, Southeast Asia, and Africa regions have the highest prevalence, with 126 million infections and no access to the new HCV drugs. However, the US and EU have 13 million chronic HCV infections, which are the target market for the new HCV drugs. Worldwide, treatment is complicated because HCV occurs in 6 major genotypes, which affect drug sensitivity and are unevenly distributed geographically and between income levels (Figure 2B).

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Figure 2. Breakdown of HCV-associated advanced liver disease in the US in 2008. (A) Time line of the development of HCV-associated liver disease. (B) Distribution of HCV genotypes by World Bank income regions. HCV has evolved into 6 major strains or genotypes that differ genetically from each other, which may result in a slightly different amino acid sequence in the region comprising and supporting the binding site of an antirviral drug. Therefore, drugs developed to inhibit genotype 1 HCV, the major genotype found in high-income and upper-middle income regions, might not inhibit genotypes found in the rest of the world such as genotypes 2–6. Panel B is taken from a poster entitled “Global distribution of HCV by prevalence and genotype” distributed by the Center for Disease Analysis (www.centerforda.com) at the 64th Annual Meeting of the American Association for the Study of Liver Diseases, Nov 1–5, 2013, Washington, DC (reproduced with permission from Homie Razavi). (C) 2008 US prevalence of HCV advanced advanced liver disease by age cohort. Upper graph: Each column breaks out the number of people with different types of advanced liver disease by age cohort (i.e., the blue box in the lower graph). The order of the types of advanced liver disease is the same for each age cohort. The number of patients (in thousands) with cirrhosis is shown in orange, decompensated cirrhosis is shown in green, liver cancer is shown in dark blue, liver transplant is shown in red, and liver cancer/transplant is shown in purple. Lower graph: Each column denotes the total number (in thousands) of people chronically infected with HCV in the US in 2008 as a function of age cohort. The upper portion of each column (dark blue) denotes the number of people with advanced liver disease.

A person can have a chronic HCV infection for decades with no obvious symptoms. Unfortunately, the longer a person is infected with HCV, the higher the chance of developing liver fibrosis, cirrhosis, failure, portal hypertension, and cancer. Typically, these symptoms occur over a period of 20–30 years (Figure 2A).

The good news is that, unlike infections with HIV and HBV, HCV can be cured. The bad news is that the majority of people infected do not know they have an HCV infection. In 2008, of the 2.68 million people in the US with chronic HCV infection, 59% were undiagnosed.(2) Figure 2C (bottom) shows the prevalence of advanced liver disease (dark blue box) in the diagnosed population as a function of age. These data reveal that baby boomers, born between 1945 and 1964, account for 75% of newly diagnosed chronic HCV patients and 84% of advanced liver disease patients. The upper graph in Figure 2B shows that the majority of advanced liver disease is decompensated cirrhosis, followed by cirrhosis. For perspective, although liver cancer represents a small fraction of advanced liver disease cases, it represents the fastest growing cancer death rate in the US. These data suggest that baby boomers are at high risk of progressing to advanced liver disease and support the CDC’s recommendation for targeted screening of this cohort.

Three Waves of HCV Drug Creation

Over the last 27 years, advances in three areas have enabled direct-acting antiviral drugs for HCV to move forward: (i) research and discovery, (ii) development, and (iii) approval and commercialization (Figure 3).

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Figure 3. HCV antiviral targets and a comparison of HCV and HIV drug creation timelines. (A) Schematic illustration of multiple steps in the HCV virus lifecycle that can be the target of an antiviral drug. IRES, internal ribosome entry site. (B) Comparison of HIV and HCV drug development time lines. POC, proof of concept; non-nuc, non-nucleotide; nuc, nucleotide; IFN, interferon alfa 2a/b; R or RBV, ribavirin; P, pegylated interferon alfa 2a/b; PR, pegylated interferon alfa 2a/b plus ribavirin.

First Wave (Research and Discovery) of HCV Drug Creation

The first wave from 1987–2002 set the foundation for the clinical development work that followed (Figure 2B). HCV replication can be inhibited at several different points in the lifecycle, by targeting either viral or host functions. As a consequence, more than 40 different treatment options are either in the market or in clinic trials; reviewed in refs 1 and 3. The crystal structures of the HCV NS3·4A protease and the NS5B RNA polymerase set a strong foundation for rational structure-based drug design, which in turn was critical for optimizing protease potency and allosteric binding. The development of the HCV replicon system in 1999(4) fueled an explosion in the scientific understanding of the HCV life cycle and enabled the development of high-throughput replicon cell-based assays. The replicon assay was used to identify a potent novel class of inhibitors that target the NS5A replication complex.(5)

Comparison of HCV and HIV Drug Development

In the past few years, rapid advances in the development of HCV drugs have looked like HIV drug development on speed, but is this a fair comparison? As shown in Figure 3, the first HIV drug was approved 3 years after the virus was identified as the etiological agent of AIDS. Since that time, the FDA approved 26 different direct-acting antiviral drugs or combinations targeting four different HIV drug targets (protease, reverse transcriptase, entry, and integrase).(1, 6) In contrast, it took 24 years after HCV was discovered for the first direct-acting antiviral drugs to be approved and 27 years for four combinations to be approved against two HCV targets (protease and polymerase).

Why Did It Take so Long for HCV DAAs to Be Developed?

Multiple factors that slowed the development of direct-acting HCV drugs included:4

• low perceived market value and a poor potential return on investment

• no tools to test the ability of compounds to inhibit HCV replication in vitro in cultured cells

• expensive licensing fees for reagents

• low pressure from patient lobbies

• a belief that all-oral treatment for HCV would never work because HCV was a liver disease, not a viral disease, and interferon would always be required.

• a poor understanding of the nature of HCV resistance to drugs led to the misconception that HCV could be successfully treated with monotherapy drugs like HSV or CMV drugs. In contrast, HCV is more like HIV and requires a multidrug combination to suppress resistant variants.

• a belief that all nucleoside/tide polymerase inhibitors are toxic, despite the fact that they are the backbone of HIV, HSV, CMV, and HBV antiviral therapy.

What Factors Increased the Speed of Research and Discovery for HCV Direct-Acting Antiviral Drugs?

The mantra of those who moved these drug combinations forward the fastest was “It’s the virus, stupid,” focusing on inhibiting HCV at multiple points in the virus lifecycle (Figure 3A) without going through a combination phase with PEGylated interferon and ribavirin. Finally, a critical, but less well-known, decision by regulatory authorities to permit drug companies to use the HCV replicon assay instead of an infectious virus assay or an animal model significantly increased the speed of development of all-oral combos.

Second Wave (Development) of HCV Drug Creation

The second wave lasted between 2003–2010 when HCV clinical virology and the clinical development path for HCV direct-acting antiviral drugs were set. The early development of the interferon-based drugs demonstrated that HCV could be cured and set the paradigm for treating a patient for a period of time after their HCV virus becomes undetectable and then monitoring for viral relapse after the end of treatment.

What Factors Increased the Speed of Developing HCV Direct-Acting Antiviral Drug Development?

With the dual goal of increasing the cure rate and reducing the duration of treatment, researchers designed novel clinical trials to explore the two parameters in the same study, rather than sequentially as had been traditional. In addition, clinical pharmacology modeling based on viral kinetics, population analyses, and pharmacokinetics was used to justify study design and to add subpopulations to the product label that were not explicitly tested. HIV research led to the use of HCV viral RNA levels as a primary end point in clinical trials, instead of following an indirect effect (ALT levels), and to the use of combinations of direct-acting antiviral drugs to combat resistance. This is exemplified by phase 3 data that revealed that three different combinations could cure patients with HCV: a protease inhibitor plus a NS5A inhibitor; a polymerase nucleotide inhibitor plus a NS5A inhibitor; and a protease inhibitor plus a polymerase allosteric inhibitor plus a NS5A inhibitor (Figure 1 and Table 1).

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Table a Three classes of HCV regimens (pegylated interferon + ribavirin (PR)), DAA + PR, and all oral DAA combos) are compared on the basis of efficacy, duration, dosing interval, dose size, price, mechanism of action (target), and compound structure. Only genotype 1 results and regimens with publically available compound structures were included. The price listed is a best-guess estimate based on publically available sources. SVR, sustained viral response; wks, weeks; DAA, direct acting antiviral; TID, 3 times a day dosing; BID, twice daily dosing; QD, once daily dosing; mg, milligram; NA, not available.

Another important factor that accelerated the development of HCV clinical study design and resistance studies was the founding of HCV DrAG, a collaboration between the major stake holders: academia, pharmaceutical companies, regulators, and community representatives.(7) HCV DrAG played a major role in facilitating the creation of new FDA and EMA guidances, which permit the combination of two or more unapproved drugs.

Short monotherapy proof-of-concept studies performed with inhibitors of HCV protease, NS5A, and HCV polymerase demonstrated that HCV replication could be inhibited in the absence of PEGylated interferon and ribavirin. Figure 3B lists some of the groundbreaking proof of concept studies. None of the development programs that were the first to demonstrate clinical proof of concept actually became approved drugs, illustrating the difficulty and risk inherent in creating drugs.

The first three HCV direct-acting antiviral drugs to be approved, telaprevir, boceprevir, and simeprevir, were protease inhibitors that had a low barrier to resistance, requiring them to be combined with PEGylated interferon and ribavirin to treat genotype 1 patients (Table 1). A nucleotide inhibitor of HCV polymerase, sofosbuvir followed, also in combination with PEGylated interferon and ribavirin for genotypes 1 and 4 patients. Sofosbuvir has a high barrier to resistance and was approved as an all-oral combination with ribavirin for patients with genotypes 2 and 3. The next two classes of compounds were polymerase non-nucleotide allosteric inhibitors (ABT-333) and NS5A replication inhibitors (daclatasvir, lepidipasvir, and ABT-267). In order to increase the barrier to resistance, the all-oral combinations shown in Figures 1 and 3 and Table 1 all include direct-acting antiviral agents with at least two different mechanisms of action. By focusing directly on developing an all-oral approach, bypassing developing a combination with PEGylated interferon and ribavirin, the time required to launch an all-oral combination was shortened.

Third Wave (Approval and Commercialization) of HCV Drug Creation

The third wave started in 2011. In this wave the FDA approved the first new antiviral regimen for chronic HCV in a dozen years. Two first generation direct-acting antiviral HCV protease inhibitors, telaprevir and boceprevir, were approved for used in combination with PEGylated interferon and ribavirin for patients with genotype 1 chronic HCV infection.(8) Patients and prescribers welcomed the greater efficacy and shorter treatment compared to PEGylated interferon and ribavirin (Figure 1 and Table 1).

It is well-known that the long path to drug approval has a high attrition rate. Only 10–20% of all compounds that enter the clinic are approved. Less well-known is the fact that 80% of approved drugs are not profitable.(9) What drives market success? Compared to boceprevir, telaprevir had similar potency, slightly better efficacy, slightly worse side effects, a simpler dosing regimen, lower pill burden, a higher price, and a newly built commercial operation. No one predicted what happened: telaprevir significantly outsold boceprevir with $2.11 billion for telaprevir vs $0.114 billion for boceprevir for the period between Q3 2011 to Q4 2012 and become the fastest drug in history to reach a billion dollars in sales. Why was telaprevir so successful? In my opinion, multiple reasons include, but are not limited to, higher efficacy, faster decline in HCV RNA in the first four weeks, lower pill burden, better dosing regimen, simpler treatment paradigm, experienced sales force and account managers, good patient copay support, and a great scientific story.

As is common with first generation drugs, there was significant room for improvement. Drawbacks of telaprevir and boceprevir included low efficacy rates in some patient populations, high pill burdens, significant serious side effects, and three times a day dosing (Table 1). The beginning of the endgame in the US and EU was revealed when Gilead announced phase 3 results, in which genotype 1 chronic HCV patients treated with 12-weeks of a once-daily fixed dose combination of an HCV polymerase nucleoside inhibitor (sofosbuvir) and NS5A inhibitor (ledipasvir) achieved a 96% cure rate.

Next Hurdle(s)

Now that potent and safe HCV direct-acting antiviral drugs are in hand, what are some of the outstanding issues?

Diagnosis and Treatment

In the US, most people with chronic HCV infection do not know they are infected. If these patients are not treated, many will develop advanced liver disease that will be costly and may be impossible to cure. An analysis of the HCV-associated nonpharmacological costs in the US between 2007 and 2009 showed that the rise in advanced liver disease more than doubled the overall growth in US healthcare costs (9.4% vs 4.3%).(2) However, if all of the currently undiagnosed people were to seek treatment, the current medical infrastructure will be overwhelmed. Now is the time to invest in diagnosis and treatment to avert a future avalanche of HCV-related advanced liver disease and associated costs.

Cost

The all-oral HCV therapy, highly efficacious and tolerable in the majority of patients, will become available in 2014. Like all new drugs, the new HCV treatment regimens are expensive. In the developed world, finding a price that works for all parties, patients, providers, payers, governments, and the pharmaceutical company, will be critical. The majority of people with chronic HCV infection do not live in the US, EU, and Japan, the primary market for current HCV drugs. We need a way to give patients in resource-poor countries access to effective HCV therapy despite their inability to pay high prices. I hope our industry will rise to the challenge to apply similar efforts to find a second Holy Grail: affordable access to curative HCV therapy for all, regardless of their country of residence or economic status.

Views expressed in this editorial are those of the author and not necessarily the views of the ACS.

The authors declare no competing financial interest.

Acknowledgment

Many thanks to Amy Juodawlkis, Rosemary Camilleri, Alan Collis, and Daša Lipovšek for editorial assistance.

Abbreviations

AIDS acquired immunodeficiency syndrome
ALT alanine liver transaminase
CMV cytomegalovirus
EMA European Medicines Agency
EU European Union
FDA US Food and Drug Administration
HBV hepatitis B virus
HCV hepatitis C virus
HCV DrAG HCV drug development group
HIV human immunodeficiency virus
NS nonstructural
RNA ribonucleic acid

This article references 9 other publications.

References

1. Clayden, P., Collins, S., Daniels, C., Frick, M., Harrington, M., Horn, T., Jefferys, R., Kaplan, K., Lessem, E., and Swan, T., 2013 Pipeline Report. In HIV, Hepatitis C (HCV), and Tuberculosis (TB) Drugs, Diagnostics, Vaccines, Preventive Technologies, Research toward a Cure, and Immune-based and GeneTherapies in Development; Benzacar, A., Ed.; HIV i-Base and Treatment Action Group: New York, 2013; p 295. http://www.pipelinereport.org (accessed January 29, 2014).

2. Zalesak, M.; Francis, K.; Gedeon, A.; Gillis, J.; Hvidsten, K.; Kidder, P.; Li, H.; Martyn, D.; Orne, L.; Smith, A.; Kwong, A.Current and future disease progression of the chronic HCV population in the United States PloS One 2013, 8 ( 5) e63959 [CrossRef], [PubMed]

3. Hunt, D.; Pockros, P.What are the promising new therapies in the field of chronic hepatitis C after the first-generation direct-acting antivirals? Curr. Gastroenterol. Rep. 2013, 15 ( 1) 303 [CrossRef], [PubMed], [CAS]

4. Lohmann, V.; Korner, F.; Koch, J.; Herian, U.; Theilmann, L.; Bartenschlager, R.Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line Science 1999, 285 ( 5424) 110– 3[CrossRef], [PubMed], [CAS]

5. Gao, M.; Nettles, R. E.; Belema, M.; Snyder, L. B.; Nguyen, V. N.; Fridell, R. A.; Serrano-Wu, M. H.; Langley, D. R.; Sun, J. H.; O’Boyle, D. R., II; Lemm, J. A.; Wang, C.; Knipe, J. O.; Chien, C.; Colonno, R. J.; Grasela, D. M.; Meanwell, N. A.; Hamann, L. G.Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect Nature 2010, 465 ( 7294) 96– 100[CrossRef], [PubMed], [CAS]

6. Flexner, C.HIV drug development: the next 25 years Nat. Rev. Drug Discovery 2007, 6 ( 12) 959– 66 [CrossRef], [PubMed], [CAS]

7. Forum for Collaborative HIV Research. HCV Drug DevelopmentAdvisory Group. http://www.hivforum.org/projects/hcv-drug-development-advisory-group.

8. Jacobson, I. M.; Pawlotsky, J. M.; Afdhal, N. H.; Dusheiko, G. M.; Forns, X.; Jensen, D. M.; Poordad, F.; Schulz, J.A practical guide for the use of boceprevir and telaprevir for the treatment of hepatitis C J. Viral Hepatitis 2012, 19 ( Suppl 2) 1– 26 [CrossRef], [PubMed], [CAS]

9. Dorato, M. A.; Buckley, L. A. Toxicology Testing in Drug Discovery and Development. In Current Protocols in Toxicology; Wiley: New York, 2007; Chapter 19, Unit 19.1.

Source

Rifaximin reduced hepatic encephalopathy events in cirrhosis

Provided by Clinical Advisor

March 25, 2014

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Patients assigned rifaximin experienced significantly fewer hepatic encephalopathy events compared with patients assigned placebo.

Rifaximin decreased hepatic encephalopathy episodes in patients with cirrhosis, new study findings show.

“[Rifaximin] is approved to treat urea cycle defects that prevent the removal of ammonia from the body,” Bruce F. Scharschmidt, MD, of Hyperion Therapeutics in San Francisco, said in a press release. “Our trial was the first to investigate the efficacy of a direct ammonia lowering agent in patients with cirrhosis and hepatic encephalopathy.”

The phase 2 study included 178 patients with cirrhosis, of which 59 were previously assigned rifaximin (XIFAXAN, Salix Pharmaceuticals). Researchers aimed to determine the proportion of patients with hepatic encephalopathy assigned twice-daily 6mL rifaximin vs. placebo.  

Patients assigned rifaximin experienced significantly fewer hepatic encephalopathy events when compared with patients assigned placebo (21% vs. 36%; P=0.02). The total number of hepatic encephalopathy events were lower in those assigned the medication (n=35) when compared with those assigned placebo (n=57).

Further, there were 13 total hospitalizations in the rifaximin arm vs. 25 hospitalizations in the placebo arm. Ammonia levels in the blood were lower in patients assigned rifaximin versus placebo.

Among those not previously treated with the drug before enrollment, rifaximin decreased the number of patients with a hepatic encephalopathy event (10% vs. 32%; P<0.01), the time to a first event (HR=0.29; P<0.01) and the total number of events (7 vs. 31; P<0.01).

“Our findings provide evidence that elevated blood ammonia plays an important role in the development of hepatic encephalopathy,” Scharschmidt said. “Rifaximin reduced the risk for hepatic encephalopathy in patients with cirrhosis and further investigation of its therapeutic potential for patients with hepatic encephalopathy is warranted.”

“The study shows that [rifaximin] improves the outcome among cirrhotic patients with highly recurrent hepatic encephalopathy,” Juan Cordoba, MD, and Meritxell Ventura-Cots, MD, both of the Hospital Vall Hebron in Barcelona, Spain wrote in an accompanying editorial. “The new drug avoids the risk for sodium overload, was well tolerated and had a good safety profile.”

References

  1. Rockey DC et al. Hepatology. 2014;59(3):1073-1083.
  2. Cordoba J. Hepatology. 2014;59(3):764-766.

Disclosure: See study for full list of disclosures.

Source

Researchers take mathematical route to fighting viruses

PUBLIC RELEASE DATE: 24-Mar-2014

Contact: David Garner
david.garner@york.ac.uk
44-019-043-22153
University of York

Mathematicians at the University of York have joined forces with experimentalists at the University of Leeds to take an important step in discovering how viruses make new copies of themselves during an infection.

The researchers have constructed a mathematical model that provides important new insights about the molecular mechanisms behind virus assembly which helps to explain the efficiency of their operation.

The discovery opens up new possibilities for the development of anti-viral therapies and could help in the treatment of a range of diseases from HIV and Hepatitis B and C to the "winter vomiting bug" Norovirus and the Common Cold. The research is published in the Proceedings of the National Academy of Sciences (PNAS).

The researchers led by Professor Reidun Twarock, of the Departments of Mathematics and Biology at York, have established a theoretical basis for the speed and efficiency with which viruses assemble protective protein containers for their genetic information – in this case an RNA molecule - during an infection.

By incorporating multiple specific contacts between the genomic RNA and the proteins in the containers, and other details of real virus infections, the research team's mathematical model demonstrates how these contacts act collectively to reduce the complexity of virus formation, thus solving a longstanding puzzle about virus assembly – a form of Levinthal's Paradox. This also ensures efficient and selective packaging of the viral genome and has evolved because it provides significant selective advantages to viruses that operate this way.

Professor Twarock, a member of the York Centre for Complex Systems Analysis (YCCSA), said: "This truly interdisciplinary effort has provided surprising insights into a fundamental mechanism in virology. Existing experimental techniques for studying viral assembly are unable to identify the cooperative roles played by all the important components, highlighting the need and power of mathematical modelling. This model is a paradigm shift in the field of viral assembly. It sheds new light on virus assembly in a major class of viruses and their evolution, and opens up a novel strategy for antiviral therapy."

Professor Peter Stockley, of the Astbury Centre for Structural Molecular Biology at the University of Leeds, added: "These results provide a new perspective for our understanding of virus assembly, highlighting important features in the process that had previously been overlooked. We have already obtained proof of principle in a simple model virus that these functions can be targeted by drugs. The new opportunities for anti-viral intervention opened up by our paper also apply to viruses for which therapeutic options are currently limited. The new approach is enticing because it enables us to target co-operative aspects of viral assembly that are conserved across different viral strains, making it less likely that drug therapy would elicit resistance mutations. "

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The research was funded by Engineering and Physical Sciences Research Council, the Biotechnology and Biological Sciences Research Council and the University of York.

Source

Liver tumors: 3-D MRI scans better predict survival after chemo

03/25/2014

In a series of studies involving 140 American men and women with liver tumors, researchers at Johns Hopkins have used specialized 3-D MRI scans to precisely measure living and dying tumor tissue to quickly show whether highly toxic chemotherapy – delivered directly through a tumor’s blood supply – is working.

The investigators say their findings, to be presented March 22-27 in San Diego at the annual meeting of the Society of Interventional Radiology, are the first “proof of principle” that this technology can show tumors in three dimensions and accurately measure tumor viability and death. Early data was also presented at the Radiological Society of North America annual meeting, December 1-6 in Chicago.

They also say their results – in patients with either primary liver cancers or metastatic tumors from cancers originating elsewhere in the body -- are evidence that using this technology before and after treatment is a faster and better tool for predicting patient survival after chemotherapy targeted directly at tumors, called chemoembolization.

Unlike standard methods to assess tumor response after chemoembolization, which are based on two-dimensional images and tumor size, the Johns Hopkins-developed 3-D technology also distinguishes between dead and live tissue, giving an accurate assessment of tumor cell death.

The new technology builds on standard 2-D methods and uses computer analytics to evaluate the amount of so-called contrast dye absorbed by tumor tissue. The dye is injected into patients before their MRI scan to enhance image production. Researchers say live tissue will absorb more dye than dead tissue, affecting image brightness, which can also be measured for size and intensity.

“Our high-precision, 3-D images of tumors provide better information to patients about whether chemoembolization has started to kill their tumors so that physicians can make more well-informed treatment recommendations,” says Johns Hopkins interventional radiologist Jean-Francois Geschwind, M.D., the senior investigator on the studies.

Geschwind, a professor in the Russell H. Morgan Department of Radiology at the Johns Hopkins University School of Medicine and its Kimmel Cancer Center, says that knowing the true extent of a tumor’s response to chemoembolization is particularly important for patients with moderate to advanced stages of the disease, whose liver tumors might initially be too large or too numerous to surgically remove.

In the first study, researchers compared the standard imaging method and the newly developed technology in 17 Baltimore men and women with advanced liver cancer. All were treated with surgery or liver transplantation after chemoembolization. The research team used existing MR analysis techniques, as well as the new 3-D method to compare the radiologists’ analyses with pathologic review of tumor samples after therapy and surgical removal. The error margin of the new 3-D image analysis, they say, was low (at up to 10 percent) when predicting the amount of dead tumor tissue found by pathologists whereas the standard, 2-D method deviated by as much as 40 percent from actual values.

In a series of additional studies, Geschwind and his team used the standard and new imaging techniques to analyze the MRI scans of more than 300 liver tumors in some 123 other men and women, also from the Baltimore region. All patients were treated at The Johns Hopkins Hospital between 2003 and 2012, and each received pre- and post-chemoembolization MRI scans to assess the effects of therapy on the tumors.

Using the new 3-D method method, Geschwind’s team found that patients who responded well to therapy lived 19 months longer (an average of 42 months) than patients who did not respond well (average 23 month survival). Standard methods showed slightly less difference in survival (average 18 months longer) between patients who responded to therapy and those who did not respond.

Geschwind says the 3-D technology’s improved accuracy removes a lot of the guesswork that now goes into evaluating treatment outcomes. The new assessment takes seconds to perform, he adds, so radiologists can provide faster, almost instantaneous treatment advice.

Geschwind and his team plan further software refinements to the new approach before training more physicians to use it. He also has plans to study how it can affect treatment decisions, and whether these therapy choices help people live longer.

The software used in the MRI scans was developed at Johns Hopkins and at Philips Research North America, in Briarcliff Manor, N.Y. Philips, whose parent company is based in the Netherlands, manufactures some of the MRI devices used in the study.

Liver cancer kills nearly 20,000 Americans each year, and is much more prevalent outside the United States, where it is among the top-three causes of cancer death in the world. Experts cite the rising numbers of hepatitis C infections, which cause chronic liver inflammation and are a leading risk factor for liver cancer.

Funding support for this study was provided by the French Society of Radiology and Philips Research North America. Additional funding support was provided by the National Cancer Institute, and the National Center for Research Resources, both members of the National Institutes of Health (R01 CA160771, P30 CA006973, and UL1 RR 025005), and the Rolf W. Günther Foundation for Radiology and Radiological Sciences.

In addition to Geschwind, Johns Hopkins scientists involved in the study were Julius Chapiro, M.D., Rafael Duran, M.D., Laura Wood, M.D., Ph.D., Vania Tacher, M.D., Toby Charles Cornish, M.D., Ph.D., Nikhil Bhagat, M.D., Constantine Frangakis, Ph.D., Hooman Yarmohammadi, M.D., Michael Chao, M.Sc., Rongxin Chen, M.D., Ph.D., Zhijun Wang, M.D., Ph.D., and Vivek Charu, M.D., Ph.D. Additional research assistance was provided by MingDe Lin, Ph.D., a Philips biomedical engineer based at Johns Hopkins who has been collaborating with Geschwind for the past seven years on the new technology.

Abstracts described in this news release include:

SIR abstracts:

1830145 Quantitative 3-D Volumetric Assessment of Tumor Response after Intra-arterial Therapy of Colorectal Cancer Metastases to the Liver - a new surrogate marker for survival;
Scientific Session TACE IV, Wednesday 3/26 - 1:39 PM - 1:48 PM, Room 16 A

1859360 Uveal Melanoma Metastatic to the Liver: the Role of Quantitative and Functional MR Imaging in the Assessment of Early Tumor Response after TACE;
Scientific Session TACE I, Sunday 3/23 - 2:42 PM - Room 16 A

1831150 Radio-pathological correlation of 3-D-quantitative contrast-enhanced and functional MRI in HCC patients after TACE- do we see what we treat?
Scientific Session TACE II, Monday 3/24 - 9:03-9:12 AM - Room 16 A

RSNA abstract:

SSSC16-07 Volumetric Tumor assessment Predicts Survival in Patients Treated with Transarterial Chemoembolization for Hepatocellular Carcinoma

For additional information, go to:
http://www.sirmeeting.org/
http://www.hopkinsmedicine.org/vascular/staff/physicians/geschwind.html
http://www.hopkinsmedicine.org/vascular/procedures/chemoembolization/

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HIV and Hepatitis C vaccines now closer to reality

Published on March 26, 2014 at 5:01 AM

Plans for a new type of DNA vaccine to protect against the deadly HIV and Hepatitis C viruses have taken an important step forward, with University of Adelaide researchers applying for a patent based on groundbreaking new research.

Professor Eric Gowans from the University's Discipline of Surgery, based at the Basil Hetzel Institute at the Queen Elizabeth Hospital, has submitted a patent application for what he describes as a relatively simple but effective technique to stimulate the body's immune system response, thereby helping to deliver the vaccine.

While pre-clinical research into this vaccination technique is still underway, he's now searching for a commercial partner to help take it to the next stage.

Professor Gowans' work has focused on utilizing the so-called "accessory" or "messenger" cells in the immune system, called dendritic cells, to activate an immune response. These are a type of white blood cell that play a key role during infection and vaccination.

"There's been a lot of work done in the past to target the dendritic cells, but this has never been effective until now," Professor Gowans says. "What we've done is incredibly simple, but often the simple things are the best approach. We're not targeting the dendritic cells directly - instead, we've found an indirect way of getting them to do what we want."

Professor Gowans and his team have achieved this by including a protein that causes a small amount of cell death at the point of vaccination.

"The dead cells are important because they set off danger signals to the body's immune response. This results in inflammation, and the dendritic cells become activated. Those cells then create an environment in which the vaccination can be successful," Professor Gowans says.

Using a micro-needle device provided by United States company FluGen Inc., the researchers can puncture the skin to a depth of 1.5mm, delivering the vaccination directly into the skin. "We chose the skin instead of the muscle tissue, which is more common for DNA vaccines, because the skin has a high concentration of dendritic cells," Professor Gowans says.

Because the technique has the potential to translate to other, more common viruses in addition to the devastating HIV and Hepatitis C, the project attracted seed funding from The Hospital Research Foundation, and additional funding from the National Health and Medical Research Council (NHMRC).

The research is still in the pre-clinical phase, with a patient study due next year. "This technique has worked much better than I anticipated," Professor Gowans says. "We're now ready for a commercial partner to help us take this to the next phase, and we're in discussions with some potential partners at the moment."

Professor Gowans will present some of his work at the forthcoming 5th Australasian Vaccines & Immunotherapeutics Development Meeting (AVID2014), 7-9 May in Melbourne, Australia. Last month he was an invited speaker at the 23rd Australian Conference on Microscopy and Microanalysis (ACMM23) in Adelaide. A paper about this work has already been published recently in Immunology & Cell Biology.

SOURCE University of Adelaide

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New genetic targets IDed for HCV treatment

Provided by Clinical Advisor

March 20, 2014

DNA changes on the IFNL3 gene have been associated with better treatment responses and natural ability to clear infection among patients with hepatitis C infection.

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Two single-letter DNA changes on the IFNL3 gene on chromosome 19 have been associated with better treatment responses and natural ability to clear infection among patients with hepatitis C infection, and may offer novel targets for therapy, according to researchers.

“[The IFNL3 gene], has received considerable attention in the field of HCV, as many independent genome-wide association studies have identified a strong association between polymorphisms near IFNL3 and clearance of HCV,” Ram Savan, PhD, assistant professor of immunology at the University of Washington in Seattle and colleagues reported in Nature Immunology. “However, the mechanism underlying this association has remained elusive.”

Previous study findings have shown that patients of Asian descent with HCV respond better to treatment when compared with those of African descent. So researchers pooled data from entire human genomes in hopes of identifying gene clusters associated with a response to therapy for HCV.

Two single-letter genetic variations on the IFNL3 gene located near an area that encodes for interleukin-28B, a cytokine known to play a role in the body's immune defense against viruses, may play a role in the body's ability to control HCV infection.

Individuals who carry the T (for thymidine) variant have an unfavorable outcome in fighting HCV, while those who carry the G (for guanosine) variant have a favorable outcome, the researchers found.

Their data showed that HCV could induce liver cells to target the activities of the IFNL3 gene with two microRNAs. MicroRNAs are silencers: They stop the messengers who transmit information to produce a protein from a gene, in this case the production of the antiviral interferon lambda-3.

These two particular microRNAs are generally turned off in liver cells, until HCV coerces them to act on its behalf. Normally, these so called myomiRs are associated with myosin-encoding genes in skeletal and heart muscle.

"This is a previously unknown strategy by which HCV evades the immune system and suggests that these microRNAs could be therapeutic targets for restoring the host antiviral response," the researchers wrote.

Adding support to this suggestion is the researchers' observation that the bad-acting microRNAs in question could not land on and repress interferon lambda-3, if the host carried the favorable "G" variant. In those cases, the host is able to escape adverse regulation by HCV, the researchers observed.

“Our data reveal a previously unknown mechanism by which HCV attenuates the antiviral response and indicate new potential therapeutic targets for HCV treatment,” the researchers concluded.

References

  1. McFarland AP et al. Nature Immun. 2014;15:72-81.

Disclosure: See study for full list of disclosures.

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