Trio Health and Express Scripts’ Accredo Specialty Pharmacy Form Collaboration

Trio Health and Express Scripts’ Accredo Specialty Pharmacy Form Collaboration to Provide Real World Evidence on Prescription Medicines across Specialty and Rare Diseases

“Our collaboration with Accredo enables us to expand on our experience analyzing real world evidence in evaluating treatments for hepatitis C, oncology, RA, hemophilia and HIV, and review medications covering a broad range of diseases and conditions that are prescribed to millions of patients and cost billions of dollars.”

Trio Health announced today that Accredo Specialty Pharmacy will collaborate with Trio Health on their proprietary technology and analytics platform to provide real world evidence of outcomes on a wide range of medicines. The collaboration is expected to bring unprecedented value-based transparency to a medication’s journey.

“Our healthcare system is comprised of patients, pharmaceutical companies, payers, physicians, pharmacy benefits managers and pharmacies, all with differing interests in terms of innovation, pricing and access to care. The ability to evaluate a complete data set encompassing patient experience and outcomes enables unparalleled insight into medication selection and value, insight that has been missing from our healthcare system,” said Brent Clough, CEO of Trio Health. “We believe once these factors become clearer, patients and biopharma innovators will benefit, as payers adopt a true performance-based model for drug reimbursement.”

Continued Mr. Clough, “Our collaboration with Accredo enables us to expand on our experience analyzing real world evidence in evaluating treatments for hepatitis C, oncology, RA, hemophilia and HIV, and review medications covering a broad range of diseases and conditions that are prescribed to millions of patients and cost billions of dollars.”

Trio Health has the ability to analyze pharmacy, physician, and clinical information within its proprietary database. The resultant patient de-identified data is harmonized to bring a new understanding of the delivery, use and outcomes of prescription medications while optimizing care of real world patients. 

https://www.businesswire.com/news/home/20190306005053/en

Collaborative Care Psychiatrists Should Play An Active Role in the Hepatitis C Epidemic

Journal of the Academy of Psychosomatic Medicine

Hepatitis C Treatment: Clinical Issues for Psychiatrists in the Post-interferon Era

Collaborative Care Psychiatrists Should Play An Active Role in the Hepatitis C Epidemic

BETHESDA, Md., March 13, 2017 /PRNewswire-iReach/ -- The mental health community is well positioned to take a more active role in Hepatitis C virus (HCV) treatment, and Psychosomatic Medicine physicians should assume a collaborative role in caring for psychiatric patients with HCV infection, according to an article published in Psychosomatics, the Journal of the Academy of Psychosomatic Medicine. "Hepatitis C Treatment: Clinical Issues for Psychiatrists in the Post-interferon Era," notes that HCV infection is a widespread and costly cause of morbidity and mortality in the United States (affecting 3.5 million people, roughly 1% of the population), and globally (affecting some 150 to 200 million persons worldwide, roughly 3% of the world population).

About 65% of people infected with HCV in the United States contracted the virus by sharing needles. Other groups at risk include those who have received blood transfusions or transplanted organs before 1992, have had sexual contact with someone with HCV infection, are on hemodialysis, are infected with HIV, are born to mothers with HCV, or work in a health care setting where accidental exposures may occur.

"Research further shows that there is a significant overlap between HCV infection and mental illness," says Yvonne Marie Chasser, M.D., Massachusetts General Hospital, Boston, and lead author of the article. HCV infection occurs at rates 10 to 20 times higher among incarcerated individuals and the severely mentally ill and is also commonly found in those who present for treatment in emergency settings, where there is a high prevalence of mental illness. One study showed that among HCV-infected patients in a hospital liver clinic setting, the rates of mental illness are significantly higher than in the general population, with schizophrenia occurring at 3.9%, bipolar depression at 2.6%, and unipolar depression at 25%.

The authors advise psychiatrists to become more familiar with HCV treatment options, particularly the new oral direct-acting antiviral regimens, which are well-tolerated and more effective than their predecessors. "Psychiatrists should be aware of the potential drug interactions among psychotropic medications and a patient's prescribed direct-acting antiviral medication," said Dr. Chasser. An online resource is provided by the University of Liverpool at www.hep-druginteractions.org.

As with any disease, the sooner treatment is initiated, the better the outcomes. However, despite the emergence of better medications, many patients face barriers due to the high cost of the drugs and the limited eligibility for treatment allowed by insurance companies. In addition, patients with severe mental illness are less likely to have access to HCV screening, diagnostic confirmation, and referral to treatment. "Because multiple barriers exist at every stage of HCV treatment, a portion of patients is lost to follow-up at each step in care," says Dr. Chasser. This phenomenon has been described in other epidemics as the treatment cascade, named for its graphical appearance of a down-going slope representing decreasing percentages of patients remaining in treatment and achieving the desired outcome.

"Because the management of interferon-induced neuropsychiatric side effects is no longer relevant due to new medications now available, psychiatrists should adopt a more proactive role, reflective of the fact that psychiatric populations carry a higher burden of HCV," suggests Dr. Chasser. Building trust is vital to the process of navigating multiple co-morbidities together.

"By optimizing a patient's mental health and reducing barriers to care, psychiatrists can improve a patient's chances of successful HCV treatment. Over time, psychiatrists will build a record of successful outcomes that will facilitate ongoing collaboration between providers and exemplify the transformative effect of integrated care," concludes the article.

The Academy of Psychosomatic Medicine, a professional society of more than 1,200 leading physicians, represents psychiatrists dedicated to the advancement of medical science, education, and health care for persons with co-morbid psychiatric and general medical conditions.

Why should we worry about conflict of interest?
Janice Boughton, MD | Physician | February 19, 2017

A recent issue of the Journal of the American Medical Association (JAMA) reads like an expose. Well, at least three of the research articles do. So exciting! I don’t want medicine — my field — to be ethically unsavory, but it is sometimes. It makes me proud to see that it polices itself and that such information is published in a high profile journal.

The third article was even more concerning from a financial standpoint. In the last few years, we have seen major changes in the way we treat hepatitis C and elevated cholesterol levels. Guidelines released in 2013 by the American Heart Association recommended that we extend the number of people who will be treated with cholesterol-lowering “statin” drugs to anyone with a 10-year risk of atherosclerotic cardiovascular disease (heart attacks and the like) of over 7.5%. Guidelines released in 2015 for the treatment of hepatitis C, a chronic liver disease caused by a blood-borne virus, suggested that we treat everyone with hepatitis C with extremely expensive drugs which, kudos to pharmaceutical researchers, can cure the disease.

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SF working on ambitious plan to eliminate hepatitis C

SF working on ambitious plan to eliminate hepatitis C

By Erin Allday, San Francisco Chronicle

February 19, 2017
San Francisco is trying to become the first city in the nation to eliminate hepatitis C, rolling out an ambitious plan that would involve curing everyone who already has it and stopping further spread of the infectious disease, which can cause severe liver damage.

Just two or three years ago, the plan, called End Hep C SF, would have been impossible. But a new cure that is effective and relatively easy to take, combined with growing enthusiasm for programs to increase access to health care, has doctors and public health officials convinced that they can wipe out the virus over the next decade.

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February 2017 - WHO guidelines on testing for chronic HBV and HCV infection

Publication details

Number of pages: 204
Publication date: February 2017
Languages: English
ISBN: 978-92-4-154998-1

Downloads
Guidelines on hepatitis B and C testing

Overview
Testing and diagnosis of hepatitis B (HBV) and C (HCV) infection is the gateway for access to both prevention and treatment services, and is a crucial component of an effective response to the hepatitis epidemic. Early identification of persons with chronic HBV or HCV infection enables them to receive the necessary care and treatment to prevent or delay progression of liver disease. Testing also provides an opportunity to link people to interventions to reduce transmission, through counselling on risk behaviours and provision of prevention commodities (such as sterile needles and syringes) and hepatitis B vaccination.

These are the first WHO guidelines on testing for chronic HBV and HCV infection and complement published guidance by WHO on the prevention, care and treatment of chronic hepatitis C and hepatitis B infection. These guidelines outline the public health approach to strengthening and expanding current testing practices for HBV and HCV, and are intended for use across age groups and populations.

Related links
More publications on hepatitis
Guidelines for the screening, care and treatment of persons with chronic hepatitis C infection
Updated version, April 2016
Guidelines for the prevention, care and treatment of persons with chronic hepatitis B infection
2015

Discovery of counterfeit hepatitis C drug is another example of why importation is bad for patients

Discovery of counterfeit hepatitis C drug is another example of why importation is bad for patients

Nicole Longo

The manufacturing and trafficking of counterfeit drugs is not just a U.S. concern but a growing threat globally. Governments around the world are working together to try to prevent these fake products from reaching and harming patients. While the U.S. market is the most secure with a closed supply chain, there remains the threat of counterfeit and adulterated drugs reaching U.S. patients. This risk increases dramatically if medicines are imported from and travel through other countries before reaching the United States because there would be no way to ensure the safety and efficacy of those products

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Ushering in an Era Where No Group Who Wants to Be Treated Should Be Excluded

Clinical Gastroenterology and Hepatology

February 2017 Volume 15, Issue 2, Pages 289–291

Ushering in an Era Where No Group Who Wants to Be Treated Should Be Excluded
Suthat Liangpunsakul, Paul Y. Kwo
DOI: http://dx.doi.org/10.1016/j.cgh.2016.09.014

Download -  Full Text Article - PDF

The landscape on the treatment of hepatitis C virus (HCV) has shifted from interferon (IFN)-based therapy to the era of all oral direct acting antiviral (DAA) therapy in December 2013 with the approval of sofosbuvir and ribavirin for HCV genotypes 2 and 3....

Continue to Full Text Article

U.S. FDA Grants Priority Review to AbbVie’s Investigational HCV Regimen of Glecaprevir/Pibrentasvir (G/P)

Priority review shortens FDA review timelines from ten months to six months. Review studies presented at the Liver Meeting, news articles, and data on glecaprevir/pibrentasvir (G/P) published in peer-reviewed journals, here.

Enanta Announces U.S. FDA Grants Priority Review to AbbVie’s Investigational HCV Regimen of Glecaprevir/Pibrentasvir (G/P) for the Treatment of Chronic Hepatitis C in All Major Genotypes (GT1-6)
                        

• If approved, G/P may provide an eight-week, once-daily, ribavirin-free cure* for HCV patients new to treatment who have any of the major HCV genotypes, without cirrhosis
• G/P includes Enanta’s second protease inhibitor, glecaprevir (ABT-493)

February 02, 2017 08:16 AM Eastern Standard Time

     

WATERTOWN, Mass.--(BUSINESS WIRE)--Enanta Pharmaceuticals, Inc. (NASDAQ:ENTA), a research and development-focused biotechnology company dedicated to creating small molecule drugs for viral infections and liver diseases, today announced that the U.S. Food and Drug Administration (FDA) has accepted AbbVie’s New Drug Application (NDA) for its investigational, pan-genotypic regimen of glecaprevir/pibrentasvir (G/P) being evaluated for the treatment of all major genotypes (GT1-6) of chronic hepatitis C virus (HCV), and has granted the NDA priority review. Glecaprevir is Enanta’s second protease inhibitor being developed through its collaboration with AbbVie and is one of the two new direct-acting antivirals in G/P.
The FDA grants priority review designation to medicines that it determines have the potential to provide significant improvements in the safety and effectiveness of the treatment of a serious disease. The NDA is supported by data from eight registrational studies in AbbVie's G/P clinical development program, which evaluated more than 2,300 patients in 27 countries across major HCV genotypes and special populations.
  
About AbbVie’s G/P HCV Clinical Development Program
AbbVie’s glecaprevir/pibrentasvir (G/P) clinical development program was designed to investigate a faster path to virologic cure* for all major HCV genotypes (GT1-6) and with the goal of addressing treatment areas of continued unmet need.
  
G/P is an investigational, pan-genotypic regimen that is being evaluated as a potential cure in 8 weeks for HCV patients without cirrhosis and who are new to treatment, who make up the majority of HCV patients. AbbVie is also studying G/P in patients with specific treatment challenges, such as genotype 3 HCV patients, patients who were not cured with previous DAA treatment, and patients with chronic kidney disease (CKD), including patients on dialysis.
  
G/P is a once-daily regimen that combines two distinct antiviral agents in a fixed-dose combination of glecaprevir (100mg), an NS3/4A protease inhibitor, and pibrentasvir (40mg), an NS5A inhibitor. G/P (300/120mg) is dosed once-daily as three oral tablets.
  
Additional information on AbbVie’s clinical trials for G/P is available at www.clinicaltrials.gov.
*Patients who achieve a sustained virologic response at 12 weeks post treatment (SVR₁₂) are considered cured of hepatitis C.

http://www.businesswire.com/news/home/20170202005659/en/Enanta-Announces-U.S.-FDA-Grants-Priority-Review

Hepatitis C Education for the Public: 31 Days of Wellness

Watch - Hepatitis C Education for the Public: 31 Days of Wellness
by Dr. Joe Galati on 01/24/2017

Dr. Joseph Galati discusses a recent presentation on hepatitis C, explaining risk factors for hepatitis C, new drug therapies for hepatitis C, and the complications associated with hepatitis C. These slides were presented at a recent program supported by the American Liver Foundation, in Houston, Texas. New therapies are able to cure hepatitis C, and if left untreated, hepatitis C can lead to cirrhosis, liver failure, liver cancer, and the possible need for a liver transplant.

Watch the video, here....

Hepatitis C and President Trump

Hepatitis C and President Trump
Lucinda Porter, RN
Formerly hep C+ nurse, author, and speaker working to make the world healthier and free of viral hepatitis

For 20 years, I’ve been advocating for people living with hepatitis C. I was diagnosed with hep C (formerly known as non-A, non-B hepatitis) in the early days of George H.W. Bush’s presidency. Clinton was president during my first treatment; George W. Bush resided during my second treatment. Obama held the office when I was cured.
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Of Interest
Health News From NPR
Republican Plan To Replace Obamacare Would Turn Medicaid Over To States
January 22, 2017
Alison Kodjak
Kellyanne Conway, a counselor to Trump, told NBC News's Sunday Today with Willie Geist, that the health care law that will replace Obamacare will turn Medicaid — a joint state-federal health insurance program for the poor — into a block grant program. The change would mean the federal government would give money to the states to implement Medicaid as they see fit.
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AASLD and IDSA clinical guidelines fall short of conflict of interest standards

MDedge
Prominent clinical guidelines fall short of conflict of interest standards

In research published online Jan. 17, Akilah A. Jefferson, MD, and Steven D. Pearson, MD, both of the National Institutes of Health in Bethesda, Md., re-examined conflict of interest disclosures for the 2013 American College of Cardiology and American Heart Association cholesterol management guideline, as well as for the American Association for the Study of Liver Diseases and Infectious Diseases Society of America’s joint 2014 guideline related to novel drug treatments for chronic hepatitis C virus (HCV) infection.

For the cholesterol guidelines, the investigators found that while the committee members fell below the threshold with only 44% reporting commercial conflicts, one writing chair had multiple conflicts until about 1 year before guideline development began, an analysis of concurrent publications suggested. For the HCV guidelines, meanwhile, 72% of the committee members reported commercial conflicts, along with four out of six committee cochairs. An analysis of concurrent publications revealed incomplete disclosure of conflicts among authors of both guidelines (JAMA Intern Med. 2017 Jan 17. doi: 10.1001/jamainternmed.2016.8439).
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NPR

From Twitter To Treatment Guidelines, Industry Influence Permeates Medicine
Two committees that developed guidelines for the management of high cholesterol and hepatitis C did not fully comply with standards set by the Institute of Medicine in 2011 to limit the number of industry-funded panelists. The Institute of Medicine required that fewer than half of guideline writers have commercial ties and that all chairs and co-chairs have no conflicts. But in both cases, at least one chairperson received money from industry and, in the case of the hepatitis C guidelines, a substantial majority of panelists also received money.

Moreover, the authors noted, when separate committees with no commercial conflicts developed guidelines for cholesterol and hepatitis C, the recommendations were more conservative and called for less expensive first-line treatments.
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Healio
Increased conflict of interest policies needed for guideline committees, advocacy organizations
The guideline for cholesterol by the American College of Cardiology and American Heart Association, as well as the guideline for hepatitis C virus treatment by the American Association for the Study of Liver Diseases and Infectious Diseases Society of America did not fully meet the Institute of Medicine standards for commercial conflict of interest management, according to studies published in JAMA Internal Medicine. The authors noted that modest or substantial industry support was common among many patient advocacy organizations, and that such support could influence their positions.
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Forbes - The U.S. Government Should Buy Gilead For $156 Billion To Save Money On Hepatitis C

The U.S. Government Should Buy Gilead For $156 Billion To Save Money On Hepatitis C

Guest post written by

Peter B. Bach and Mark Trusheim

The U.S. government could cure most Americans suffering from hepatitis C infections if it simply bought drug maker Gilead Sciences on the stock market rather than purchasing its products in the drug market.
Gilead has drawn fire for the high price of its hepatitis C drugs, Sovaldi and Harvoni, which currently cost more than $500 per pill but cure the underlying hepatitis C liver infection. But, counterintuitively, buying Gilead outright on the open market could lower hepatitis C drug costs per patient to one-third their current level. That would make it affordable to rapidly treat the 2.7 million Americans the CDC estimates still have hepatitis C....

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Family Practice News - Hepatitis outlook: December 2016

Family Practice News - Hepatitis outlook: December 2016
Richard Pizzi Frontline Medical News
Publish date: January 6, 2017

If you work on the front lines of medical care treating patients with hepatitis, you may not have time to review all the hepatitis research that enters the medical literature every month. Here’s a quick look at some notable news items and journal articles published over the past month, covering a variety of the major hepatitis viruses.

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Of Interest

January HCV Newsletters - What's New in 2017

Greetings everyone, welcome to this months index of 2017 Newsletters; read about promising new hepatitis C drugs in development, liver transplantation for viral hepatitis, screening patients for liver cancer and a look back at the most popular stories of 2016.

January 2017 - From HCV To HBV Cure

Special Issue: Liver International

Proceedings of the 10th Paris Hepatitis Conference. International Conference on the Management of Patients with Viral Hepatitis undefined

Volume 37, Issue S1
January 2017
Pages 7–12

From HCV To HBV Cure (pages 73–80)
Raymond F. Schinazi and Tarik Asselah
Version of Record online: 3 JAN 2017 | DOI: 10.1111/liv.13324
Article
PDF(427K)

Abstract

Approximately 170 million people are chronically infected with HCV and 350 million are chronically infected with HBV worldwide. It is estimated that more than one million patients die from complications related to chronic viral hepatitis, mainly HCC which is one of the most frequent cancers in many countries, especially Africa, the Middle East and Asia. HCV drug development has been impressive, and this revolution led to several direct-acting antiviral agents achieving an HCV cure after only 6-12 weeks. This progress could theorically lead to HCV global elimination making HCV and its consequences a rarity. HBV research and development programs can learn from the HCV experience, to achieve an HBV functional or sterilizing cure. This review will summarize key steps which have been realized for an HCV cure, and discuss the next steps to achieve for an HCV elimination. And also, how this HCV revolution has inspired scientists and clinicians to achieve the same for HBV.

Key Points
HCV cure

• Combining DAAs results in high SVR (>95%) and short duration (6-12 weeks).
• Shortened duration treatments (3-8 weeks) are under evaluation.
• HCV elimination requires improvement in screening, prevention and access to treatment.

HBV cure

• The new goal of HBV therapy is to achieve a “virological cure” with HBsAg loss/seroconversion and cccDNA clearance.

• cccDNA is an excellent target, since elimination/control of cccDNA leads to HBV cure.

• Inhibitors of nucleocapsid inhibit formation and assembly of core particles leading to the failure of mature viron production as well as blocking cccDNA replenishment.

1 Major steps toward HCV elimination

1.1 The replicon system has been an important tool to evaluate direct-acting antiviral agents (DAAs)

HCV, identified in 1989, is an enveloped virus with a 9.6 kb single-stranded RNA genome,[1] a member of the Flaviviridae family, genus Hepacivirus. The development of a subgenomic HCV RNA replicon capable of replication in the human hepatoma cell line, Huh 7, has been a significant advance in this field.[2, 3] This replicon model, together with other replicon-based systems improve our understanding of HCV replication as well as resistance and allow evaluation of potential antiviral molecules for efficacy and cytotoxicity using real-time PCR. The HCV replication cycle begins with virion attachment to its specific receptor. The HCV RNA genome serves as a template for viral replication and as viral messenger RNA for viral production. It is translated into a polyprotein that is cleaved by proteases. Viral assembly then occurs. Potentially, each step of the viral replication cycle including viral entry is a target for drug development. Knowledge of the structures of HCV protease and HCV polymerase has allowed structure-based drug design to develop inhibitors to these enzymes.[4, 5]

1.2 Direct-acting antivirals (DAA)

The proof-of-concept for the first DAA (a protease inhibitor) was developed in 2002, and was a revolution in HCV drug discovery.[6, 7] All the HCV enzymes—NS2-3 and NS3-4A proteases, NS3 helicase and NS5B RdRp—are essential for HCV replication, and are potential drug discovery targets. In addition, NS5A DAA have produced picomolar HCV inhibitors such as Daclastavir. Therefore, DAA with different viral targets, including NS3 protease inhibitors, nucleoside/nucleotide analogs and non-nucleoside inhibitors of the RNA-dependent RNA polymerase and NS5A inhibitors, were developed.[8] There is a strong rational to combine different DAA for HCV treatment. This allows high efficacy, reduced risk of resistance and reduced duration of treatment. High priorities achieved with DAA are listed in Box 1.

Box 1. Top Priorities for Direct-Acting Antivirals

1.3 Protease inhibitors

The NS3 serine protease is located in the N-terminal region of NS3. The NS3 serine protease domain is associated with the NS4A cofactor to cleave four specific sites. This enzyme has been extensively characterized at the biochemical level and its structure is known.[4, 5] The serine protease activity of NS3 is an attractive target for new drugs that could effectively block viral replication. The NS3/4A protease inhibitors can be divided into two chemical classes: macrocyclic inhibitors and linear tetra-peptide a-ketoamid derivatives. In 2003, a macrocyclic protease inhibitor (BILN 2061; ciluprevir) that blocks HCV replication in the replicon model was shown to be effective in humans.[6, 9]
Although first-generation protease inhibitors are potent, they have several potential limitations. Protease inhibitors are highly specific and as the amino acid sequence of the NS3 protease domain differs significantly between HCV genotypes, they exhibit varying activities across genotypes. The genetic barrier to resistance is defined as the number of amino acid substitutions required to confer full resistance to a drug. Usually, DAA with a low genetic barrier to resistance require only one or two amino acid substitutions for high resistance. DAA with a high barrier to resistance usually require three or more amino acid substitutions in the same region to confer loss of activity.

The main weaknesses of the first-generation PIs were their low genetic barrier to resistance and the fact that their effectiveness was limited to GT-1 patients. Second-wave PIs have a higher barrier to resistance, better potency against multiple genotypes, more convenient dosing schedules and improved safety and tolerance. Second-generation PIs are broadly active against all genotypes and against viral isolates that carry resistance mutations for first-generation PIs. In combination with NA, the new PIs appear to achieve greater SVR rates than the first-generation PIs. These new treatments allow for more convenient administration schedules (one or two administrations per day); this could result in improved pharmacokinetics and better patient compliance. Besides, the safety profile seems to be good. The pan-genotypic activity of these new treatments provides new therapeutic options for a greater number of patients, in particular for those infected with GT-4.[10]

1.4 Polymerase inhibitors

Nucleoside polymerase inhibitors in their 5′-triphosphate form interfere with viral replication by binding to the NS5B RNA-dependent RNA polymerase. NS5B RNA polymerase inhibitors can be divided into two different types—nucleoside inhibitors (NI) and non-nucleoside inhibitors (NNI). NI mimic the natural substrates of the polymerase and are incorporated into the RNA chain causing direct chain termination.[11] NI require bioconversion to an active triphosphate form. As the active site of NS5B is highly conserved, NI are generally pan-genotypic (effective against all the different genotypes). However, single amino acid substitutions in every position of the active site may result in loss of function of the NI, but resistance to nucleoside analog inhibitors is typically very low in humans as this virus has reduced fitness.
In contrast, NNI bind to several discrete sites outside of the HCV polymerase active centre, which results in conformational protein change before the elongation complex is formed.[11] NS5B is structurally organized in a characteristic ‘right-hand motif’ containing finger, palm and thumb domains, and offers at least four NNI-binding sites, namely, benzimidazole (thumb 1)-binding, thiophene (thumb 2)-binding, benzothiadiazine (palm1)-binding and benzofuran-(palm 2)-binding sites. Resistance is more frequent with NNI compared with NI. However, mutations at NNI-binding sites do not necessarily lead to impaired function of the enzyme.

1.5 NS5A inhibitors

The NS5A is a membrane-associated phosphoprotein present in basally phosphorylated (p56) and hyperphosphorylated (p58) forms.[12, 13] It was previously reported that only p58-defective mutants could be complemented in trans, and NS5A is involved in HCV virion production, suggesting that different forms of NS5A exert multiple functions at various stages of the viral replication cycle.[12, 13] The N terminus of NS5A (domain I) has been crystallized in alternative dimeric forms and contains both zinc- and RNA-binding domains, properties that have been demonstrated in vitro. NS5A has been shown to interact with a number of host proteins and plays a role in interferon resistance in vivo.[12, 13] Daclastavir is active at picomolar concentrations in vitro in HCV replicons expressing a broad range of HCV genotypes and acts in an additive to synergistic fashion with interferon and other DAA.[12, 13] The resistance profile of daclastavir reveals inhibitor sensitivity maps to the N terminus of domain 1 of NS5A.[14] It has been demonstrated that NS5A inhibitors could block hyperphosphorylation of NS5A, which is believed to play an essential role in the viral replication cycle.

2 What are the Goals obtained by achieving sustained virological response?

A remarkable revolution has been recently achieved with the availability of DAA with high chance to cure and good tolerability. The primary goal of treatment is to achieve a sustained virologcal response (SVR) which is usually defined as undetectable serum HCV RNA 12 weeks after the end of treatment.[15] The SVR has been shown to be durable on long-term follow-up and associated with the eradication of HCV infection confirmed by undetectable HCV RNA in serum and the liver.[16] An SVR indicates that viral infection has been cured. In addition, viral eradication is associated with the regression of fibrosis, the possible reversibility of cirrhosis as well as significant improvement of the clinical outcome and survival with a decreased incidence of complications, especially HCC. Goals obtained by achieving an SVR are listed in Box 2.
Patients with cirrhosis treated with DAAs should continue to be closely monitored for HCC (ultrasound each 6 months). Surveillance is also advocated in SVR patients with any histological stage of hepatitis C who carry comorbidities as alcohol cunsomption and diabetes, which are well-recognized independent risk factors for HCC. The benefit of treating HCV in patients with past or present HCC is under evaluation.

Box 2. Goals obtained by achieving Sustained Virological Response (SVR) ≈ cure

Eradicate the virus (HCV clearance)
Reduce Necroinflammation
Stop Fibrosis progression
Prevent Cirrhosis & complications
Prevent Hepatocellular carcinoma
Reduce extra-hepatic manifestations
Increase Survival

3 What are the Gaps to achieve HCV elimination ?

HCV elimination is an achievable goal, since several, all oral, IFN-free DAA combinations are now able to cure HCV in more than 95% of HCV infected individuals after 8-12 weeks of treatment. The programme to eradicate HCV must include increased screening (universal), linkage to care, as well as increased access to treatment worldwide (Box 3). Reducing DAAs cost will also be important.[17]
Real-life data on treatment efficacy, tolerability and adherence are mandatory. Compliance to drug regimens will become a major issue to avoid failure.

Box 3. Strategies for HCV elimination

How far we can go with shortened treatment duration remains to be studied (2, 3, 4, 6 or 8 weeks). However a pilot study conducted in China in genotype 1b patients with three potent DAA (NA, NS5A and PI) resulted in 100% SVR.[18] Patients who failed previous treatment and developed resistance-associated variants (RAV) to NS5A, should be rescued with future combinations.

3.1 HBV infection
Chronic hepatitis B (CHB) infection affects over 400 million people worldwide, with long-term morbidity such as cirrhosis and hepatocellular carcinoma (HCC) accounting for around 600,000 deaths annually.[19] Fibrosis is the most important prognosis predictor. Serum biomarkers to diagnose fibrosis are under development.[20]
In the sixties, Blumberg identified the hepatitis B virus (Australia antigen (Ag)).[21, 22] Rapidly after the identification of hepatitis B, vaccines were a large success.[23-26] Blumberg was awarded the Nobel Prize in Medicine in 1976 for both the description of HBV and the notion of a life saving effective HBV vaccine.

3.2 HBV Current therapy

The goal of therapy for CHB is to improve quality of life, preventing viral transmission, and survival by preventing progression to severe disease and HCC.[27] Previously, HBV DNA suppression with long-term lamivudine (LAM) was associated with a reduction in the incidence of hepatic decompensation and HCC.[28, 29] Treatment goals can be achieved by sustained suppression of HBV replication, thereby reducing the histological activity of CHB and reducing the risk of fibrosis progression. Suppression of HBV replication is critical, but must be maintained if optimal treatment outcomes are to be achieved. Currently, there are two main treatment strategies for both hepatitis B “e” (HBe) antigen-positive (HBeAg+ve) and antigen-negative (HBeAg-ve) patients: two finite treatment courses of interferon alpha (IFN)/pegylated IFN (PEG-IFN) or long-term therapy with nucleoside analogs (NA). A one year treatment with PEG-IFN offers the potential for immune-mediated control of HBV infection, with higher rates of HBe seroconversion and the possibility of off-treatment viral suppression, with loss of hepatitis B surface antigen (HBsAg) in a proportion of patients who maintain undetectable HBV DNA. However, PEG-IFN needs to be administered by subcutaneous injection and is associated with frequent side effects such as depression; it is also contraindicated in patients with decompensated cirrhosis or relevant autoimmune disease, during pregnancy.

In contrast, NA suppress HBV by direct antiviral activity, and if compliance to treatment is good, more than 95% of patients treated with the newer, highly potent NA tenofovir disoproxil fumarate (TDF) and entecavir (ETV) achieve virological remission. NAs are administered orally, and tolerance is good, although the safety of these drugs over lifelong therapy is unknown. One potentially serious drawback of long-term NA therapy is potential renal toxicity (in the cse of TDF) and the development of drug resistance; however, although common with earlier less potent NA such as lamivudine (LAM) and adefovir (ADV), resistance has become considerably less of a problem with the highly potent NA TDF and ETV.

4 HBV current therapy: What have we learned recently?
4.1 Long-term efficacy and real-world data
Long-term clinical data up to 6 years and beyond are emerging for the newer NA that are providing reassuring data on their efficacy and safety. There is cumulative evidence that complete long-term suppression of HBV replication by the most potent drugs (ETV and TDF) results in an improved long-term outcome with a decreased risk of progression to cirrhosis and complications such as liver failure, HCC and improved survival. In addition, a recent study assessing liver histology in patients treated with TDF for 5 years demonstrated that fibrosis regressed in most patients.[30, 31] Moreover, unlike what is generally believed, the reversal of cirrhosis was observed during treatment in 75% of patients with cirrhosis, probably associated with a decreased risk of HCC and improved survival. Further long-term data are emerging from studies using newer potent NA in routine clinical practice confirming safety and efficacy of these agents in the “real-world” setting.

4.2 Combination therapy (TDF plus PEG-IFN)

In a recent study, Marcellin et al.[32] evaluated HBsAg loss in patients receiving the combination of TDF and PEG-IFN for a finite duration. In an open-label, active-controlled study, 740 patients with CHB were randomly assigned to receive TDF plus PEG-IFN for 48 weeks (group A), TDF plus PEG-IFN for 16 weeks followed by TDF for 32 weeks (group B), TDF for 120 weeks (group C), or PEG-IFN for 48 weeks (group D). At week seventy-two, 9.1% of subjects in group A had HBsAg loss compared with 2.8% of subjects in group B, none of the subjects in group C, and 2.8% of subjects in group D. A significantly higher proportion of subjects in group A had HBsAg loss than in group C (P<.001) or group D (P=.003). However, the proportions of subjects with HBsAg loss did not differ significantly between group B and group C (P=.47) or group D (P=.88). HBsAg loss in group A occurred in hepatitis B e antigen-positive and hepatitis B e antigen-negative patients with all major viral genotypes.

Finally, a significantly greater proportion of patients receiving TDF plus PEG-IFN for 48 weeks had HBsAg loss than those receiving TDF or PEG-IFN alone.

4.3 Can we stop therapy of nucleosides?

The European Association for the Study of the Liver (EASL)[27] and the American Association for the Study of Liver Disease (AASLD) guidelines[33] suggest HBsAg loss as the ideal end point for oral therapy. However, this rarely occurs and is mainly seen in HBeAg-negative patients. Therefore, patients should probably be treated for life. On the other hand, the Asian Pacific Association for the Study of the Liver (APASL) recommendations[34] for stopping NA are sustained suppression of HBV replication, (three measurements showing HBeAg loss or undetectable HBV DNA within 1 year), which is frequent during NAs therapy. Thus, one of the key issues when monitoring patients who are receiving NA therapy is when can patients stop therapy with no risk of relapse?
The retrospective study by Chen et al.[35] in HBeAg-positive and negative patients reports that end of treatment HBsAg levels <300, 300-1000 and >1000 UI/mL in HBeAg-positive patients were associated with sustained HBeAg loss in 55.6%, 7.7% and 3.3%, respectively. EOT HBsAg cut-offs <120, 120-1000 and >1000 IU/mL in HBeAg-negative patients were associated with HBsAg loss in 79.2%, 14.3% and 0%, respectively, and HBsAg cut-offs <200, 200-1000 and >1000 IU/mL were associated with an SVR in 93%, 11.1% and 15.4%, respectively. Similar results were reported in patients whose treatment was discontinued according to APASL guidelines. An end of treatment HBsAg level <100 IU/mL was associated with high SVR, while >1000 IU/mL was associated with a 1 year post-treatment relapse in 70%.[36-38]

4.4 HBsAg quantification: a new tool for HBV monitoring

Quantifying HBsAg is certainly an important new tool for predicting the severity of disease, to distinguish inactive carriers from patients with HBeAg-negative chronic active hepatitis; and also help tailor follow-up and treatment management.[39, 40] In addition, a decline in quantitative HBsAg during therapy is a strong predictor of SVR after PEG-IFN therapy and of the probability of HBsAg loss, which is the ultimate goal of therapy.[41] In patients treated with analogs, a decline in HBsAg levels is also a predictor of HBsAg loss, allowing therapy to be discontinued.

4.5 Future strategies

There is considerable interest in the potential for finite therapy in patients following successful HBsAg seroconversion. Studies are underway to determine if it is possible to successfully combine the potent effects of NA with an immunomodulatory therapy to allow more patients to stop therapy. Furthermore, there are three drugs, which are all prodrug of tenofovir, in development. Among these, tenofovir alafenamide, or TAF, is already approved in the USA for HIV treatment.

5 Knowledge of HBV replication cycle is important for drug development to identify targets. Goals of therapy is to obtain a virological cure, or at least a functional cure

HBsAg synthesis during the HBV viral replication cycle is complex and usually occurs in the endoplasmic reticulum.[42, 43] Upon entry into the hepatocyte the virion sheds its protein coat and its genome is transported into the nucleus where it resides as stable fully double stranded cccDNA and acts as a template for the transcription of the viral gene.[44] HBsAg is translated from mRNA with the transcriptional template-active cccDNA, which is the reflection of the number of infected hepatocytes. The clinical relevance of HBsAg levels is inferred from the relationship of this marker to the intrahepatic amount of cccDNA. There is a correlation between serum HBsAg concentrations and the intrahepatic levels of cccDNA, with the highest levels occurring in HBeAg positive hepatitis B and the lowest in patients with resolved hepatitis.[45-47] Through this association, the amount of circulating HBsAg is thought to indirectly measure the control of infection by the immunological response independent from the antiviral response, which can be assessed by measuring HBV DNA levels in serum. Serum HBsAg can be considered to be a surrogate marker of the number of infected cells.

Since NA cannot eliminate cccDNA, persisting in the nucleus of hepatocyte, HBV infection cannot be cured. Currently, there are many compounds in development for chronic hepatitis B, and they can be categorized into two groups.
The DAA and the host-targeting antiviral agents (HTA). Goals to achieve for future treatment are listed in Box 4.[48]

Box 4. Definition of a cure
Functional cure

• Sustained off-drug suppression of serum HBsAg, HBeAg, viral DNA, and cccDNA.
• Normalization of liver function (normal levels of serum ALT and AST).
• Comparable with individuals with naturally resolved infection.

Absolute cure—virologic cure

• Sustained off-drug suppression of serum HBsAg, HBeAg, and viral DNA.
• Normalization of liver function (normal levels of serum ALT and AST).
• Elimination of cccDNA.
• Presence of HBsAb.
• Comparable with uninfected individuals

5.1 Entry inhibitors

Yan et al.[49] reported in 2012 that sodium taurocholate cotransporting polypeptide (NTCP) is a major functional receptor for HBV (and HDV) to enter the hepatocyte. Yan et al. started by isolating primary liver cells from treeshrews, and then used a combination of advanced purification and mass spectrometry analysis to show that the NTCP on the surface of the cells interacts with the pre-S1 domain in HBV. The authors then performed a series of gene knockdown experiments on liver cells of both human and treeshrew origin: when the gene that codes for NTCP was silenced, HBV infection was greatly reduced. Moreover, they were able to transfect HepG2 cells—which are widely used in research into liver disease, but are not susceptible to HBV and HCV infection—with NTCP from humans and treeshrews to make them susceptible.
Myrcludex-B is a synthetic lipopeptide that is derived from pre-S1 domain of HBV envelope protein.[50, 51] Since it contains NTCP-binding pre-S1 domain of HBV envelope protein, it competitively binds to NTCP, thereby inhibit attachment of HBV to NTCP. Currently Myrcludex-B is in Phase II clinical trial, and there are other drugs under investigation, such as cyclosporine A and ezetimibe.

5.2 Capsid effectors: nucleocapsid assembly inhibitors affect cccDNA

These drugs inhibit formation and assembly of core particles leading to the failure of mature viron production as well as blocking cccDNA replenishment (Table 1). cccDNA is an excellent target, since to achieve HBV cure, elimination, suppression or control of cccDNA is warranted (Box 5).[52, 53]

Table 1. DAAs: Inhibitors of nucleocapsid assembly

Drug name	Target	Compound	Stage of development
GLS4	Interfere with capsid formation/ stability	Heteroaryldihydropyrimidine (HAPs)	Phase II
Bay 41-4109	Viral nucleocapsid inhibitor	HAPs	Phase I
AT-130	Inhibition of HBV capsid assembly	Phenylpropenamide derivatives	Preclinical and early clinical phase
NVR-3-778 (NVR1221)	Inhibition of HBV capsid assembly	Small molecule	Phase Ib

Box 5. Relevance of cccDNA as a targuet

• cccDNA persistence is the cause of chronic HBV disease
• cccDNA exists as a minichromosome in the nucleus
• cccDNA persists in the absence of active viral replication
• cccDNA levels reduced, but not eliminated with treatment/ liver regeneration
• HBV Cure: elimination, suppression or control of cccDNA

Capsid effectors disrupt the capsid and indirectly affect the stabiity of cccDNA, by inhibiting the formation of cccDNA, and/or destroying the cccDNA per se. However, only three of these drugs (from Novira now J&J, and a Chinese company) have progressed to clinical trials, but many others are in early preclinical phases.[54-56] GLS4 is currently in Phase II study, and the results are awaited.[54] NVR 3-778 is a small molecule that inhibits the HBV capsid protein by oral administration.[56] Oral HBV core inhibitor NVR 3-778 appears to be effective against HBV with synergistic activity when combined with NA.

5.3 DAA: RNA interference

There are several RNA interference drugs under clinical trial. ARC-520, which is currently in Phase II/III trial, is a compound that contains HBV mRNA-targeting siRNA.[57] Upon administration, the siRNAs in ARC-520 associates with the viral mRNA and forms a double-stranded RNA, leading to degradation. Therefore, it can reduce the production of viral protein and viral replication per se.
The product targets highly conserved regions of all five of the mRNAs produced by HBV. This approach potentially interferes with the production of all of the viral proteins, as well as the stability of the pre-genomic RNA that the virus uses as a template for DNA synthesis. ARC-520 is claimed to have a dual mechanism of action, both reducing viral replication and restoring the immune system's ability to clear the infection from hepatocytes.
A recent report of the phase IIa trial has shown that a single injection of ARC-520 resulted in significant reduction in HBsAg for up to 43 days. When given as a single, IV administration, ARC-520 was well tolerated up to and including a dose of 3 mg/kg in CHB subjects, who were also receiving entecavir, and up to 4 mg/kg in normal volunteers.[57] A single injection of ARC-520 resulted in significant reduction in HBsAg for up to 43 days.

5.4 Gene editing approaches: CRISPR/Cas 9

Using lentiviral transduction of a bacterial Cas9 gene and single guide RNA (sgRNA) specific for HBV, effective inhibition of HBV DNA production in in vitro models of both chronic and de novo HBV infection can be observed. Cas9/sgRNA combinations specific for HBV can reduce total viral DNA levels by up to 1,000-fold and HBV cccDNA levels by up to 10-fold and also mutationally inactivates the majority of the residual viral DNA.[58, 59]

6 Conclusions

There has been a revolution in the treatment of HCV infection. Several oral regimens combining direct-acting antiviral (DAA) agents result in an increase in SVR rates to above 95% and reduce the duration of treatment from 12 to 8 weeks. Remaining issues will include increasing screening and access to care so that HCV may become the first chronic viral infection eradicated worldwide.
There is increasing research in the field of HBV infection. The new goal of HBV therapy is to achieve a “functional cure” or even “absolute cure” with HBsAg loss/seroconversion and clearance of cccDNA. New agents (DAA and HTA) for CHB are starting to emerge: HBV entry inhibitors, small interfering RNA, capsid inhibitors, CRISPR/Cas9 are promising, but early in development. New drugs aimed to decrease or eliminate cccDNA and/or HbsAg are promising.

Conflicts of Interest

Raymond Schinazi is the founder and major shareholder of Cocrystal Pharma, Inc. Tarik Asselah is a speaker and investigator for AbbVie, BMS, Boehringer-Ingelheim, Tibotec, Janssen, Gilead, Roche and MSD.

http://onlinelibrary.wiley.com/doi/10.1111/liv.13324/full

2016/2017 - New HCV two and three drug regimens on their way: what do they promise?

Summary for AASLD 2016 for Hepatitis C - New HCV two and three drug regimens on their way: what do they promise? And what do clinicians need to look out for under DAA combination therapy and beyond SVR?
Jurgen K. Rockstroh M.D., Professor of Medicine University of Bonn, Germany

Jules Levin Executive Director of National AIDS Treatment Advocacy Project (NATAP) recently added this complete summary of AASLD 2016 including links to each study cited in the article. Here is a summary of the topics and introduction with a few links of interest, click here to view the full text article.

Topic Summary
Risk of HBV reactivation after starting DAA therapy
Surveillance for hepatocellular carcinoma (HCC) and risk for HCC after achieving SVR following DAA therapy.
Intravenous drug users and patients on opioid substitution therapy
Patients in the prison setting
HIV/HCV coinfected patients
Patients with renal insufficiency or on hemodialysis
Patients older than 70 years
Patients receiving short treatment durations of 8 week
HCV three drug rescue combinations with licensed drugs
New dual DAA combinations
New three drug combinations

Introduction
At present, besides the Abbvie 3-D regimen, mostly dual hepatitis C (HCV) direct acting antiviral (DAA) combinations which are coformulated as single tablet regimens have become the gold standard for first line treatment of all HCV genotypes. Despite SVR rates on average above 95% there are still attempts in the field to develop three drug combinations (so called triplets) or very potent new dual regimens which may allow shortening of treatment duration and may also add to the antiviral pangenotypic activity of all oral DAA combination therapy. Obviously, even with the currently licensed HCV drugs, three drug combinations may play a role in retreatment of the few patients which experience virological failure under dual DAA-based HCV therapy. Various studies at AASLD this year where devoted to effectiveness and safety of these new three DAA regimens in treatment naïve as well as treatment experienced patients including prior DAA-based treatment failure (1-7). In addition, data on the new and very potent Abbvie dual combination (Glecaprevir (ABT-493)/Pibrentasvir (ABT-530)), again in treatment-naïve, experienced- and prior DAA-failures, was presented (8-10). Another important topic was feedback on safety and effectiveness of various all oral DAA combinations from real-world cohorts including a whole variety of special populations including intravenous drug users, patients on opioid substitution therapy, patients in the prison setting, HIV coinfected, patients with renal insufficiency, patients older than 70 years, patients receiving short treatment durations of 8 week and much more (11-19). As more and more data arises from very diverse patient populations it appears as if no special or hard to treat patient group seems to exist any longer. In the end it really is more about getting access to therapy feasible for some of those more marginalized patient groups. A further important topic was around clinically relevant issues which clinicians who treat HCV need to be aware of, including risk for hepatitis B (HBV) reactivation after starting DAA therapy, as well as the risk for development of hepatocellular cancer (HCC) after achieving SVR (20-24). Although HCV remained to be a widely recognized topic throughout AASLD, it is becoming apparent that other topics in hepatology including NASH, alcoholic hepatitis, hepatitis B, HCC and primary biliary cholangitis are gaining importance and presentation space especially in the late-breaker session. A more intensified discussion on national HCV screening programs, HCV treatment uptake and linkage to care at AASLD would be desirable to politically underline the need to continue the fight to ensure global access of HCV therapies throughout the world.

View full text article with slides over at National AIDS Treatment Advocacy Project (NATAP)

Of Interest
Hepatitis C Hot Topics - Research and News of 2016
Take a look back at the top HCV news stories of 2016. Sit back and review a collection of hepatitis C research articles, guideline updates, conference reports, learning activities, and news from around the web

AbbVie Awaits NDA Approval For Hepatitis C Treatment
Dec. 19, 2016
AbbVie (ABBV), a global biopharmaceutical company, announced that it has submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for the company's investigational, pan-genotypic regimen of glecaprevir/pibrentasvir (G/P), being evaluated for the treatment of chronic hepatitis C virus (HCV).

Gilead Submits NDA to FDA for Sofosbuvir/Velpatasvir/Voxilaprevir HCV Genotype 1-6
December 8, 2016
Gilead Submits New Drug Application to U.S. Food and Drug Administration for the Investigational Single Tablet Regimen Sofosbuvir/Velpatasvir/Voxilaprevir
- If Approved, SOF/VEL/VOX Would Be the First Once-Daily Single Tablet Regimen Available as a Salvage Therapy for Patients Infected with HCV Genotype 1-6 Who Have Failed Prior Treatment with DAA Regimens Including NS5A Inhibitors -

Hepatitis C Hot Topics - Research and News of 2016

Hepatitis C Hot Topics - Research and News of 2016

Today we take a look back at the top HCV news stories of 2016. Sit back and review a collection of hepatitis C research articles, guideline updates, conference reports, learning activities, and news from around the web.

Recent News
AbbVie Awaits NDA Approval For Hepatitis C Treatment
Dec. 19, 2016
AbbVie (ABBV), a global biopharmaceutical company, announced that it has submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for the company's investigational, pan-genotypic regimen of glecaprevir/pibrentasvir (G/P), being evaluated for the treatment of chronic hepatitis C virus (HCV). In Phase 3 clinical studies, eight weeks of therapy with G/P achieved high sustained virologic response (SVR) rates across all major genotypes (GT 1-6) in patients without cirrhosis, which represents the majority of HCV patients. In patients with compensated cirrhosis, high SVR rates were achieved after 12 weeks of therapy. High SVR rates were also achieved in patients with limited treatment options, such as those with severe chronic kidney disease (CKD). In historically difficult to treat populations, including those not cured* by prior direct-acting antiviral (DAA) treatment regimens, high SVR rates were achieved with durations as short as 12 weeks.

Of Interest
Press Release
Nov 11, 2016
Eight Weeks of Treatment with AbbVie's Investigational, Pan-Genotypic Regimen of Glecaprevir/Pibrentasvir (G/P) Achieved High SVR Rates Across All Major Genotypes of Chronic Hepatitis C
NORTH CHICAGO, Ill., Nov. 11, 2016 /PRNewswire/ -- AbbVie (NYSE: ABBV), a global biopharmaceutical company, today announced high SVR₁₂ rates with 8 weeks of treatment with its investigational, pan-genotypic regimen of glecaprevir (ABT-493)/pibrentasvir (ABT-530) (G/P) across all major chronic hepatitis C virus (HCV) genotypes. In more than 700 genotype 1-6 (GT1-6) chronic HCV infected patients without cirrhosis and who are new to treatment, 97.5 percent (n=693/711) achieved sustained virologic response at 12 weeks post treatment (SVR₁₂), regardless of baseline viral load. The rate of virologic failure was 1 percent (n=9/711).

November 13, 2016
Glecaprevir/Pibrentasvir: High SVR Rates in HCV GT 2, 4, 5, 6 Without Cirrhosis

Dec 8, 2016

Gilead Submits New Drug Application to U.S. Food and Drug Administration for the Investigational Single Tablet Regimen Sofosbuvir/Velpatasvir/Voxilaprevir
Gilead Sciences, Inc. announced that it has submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for an investigational, once-daily single tablet regimen containing sofosbuvir 400 mg, velpatasvir 100 mg, and voxilaprevir 100 mg (SOF/VEL/VOX) for the treatment of direct-acting antiviral (DAA)-experienced chronic hepatitis C virus (HCV)-infected patients. The data submitted in the NDA support the use of the regimen for 12 weeks in DAA-experienced patients with genotype 1 to 6 HCV infection without cirrhosis or with compensated cirrhosis.

Of Interest
October 2016
Gilead Announces SVR12 Rates From Four Phase 3 Studies of a Once-Daily, Fixed-Dose Combination of Sofosbuvir, Velpatasvir and Voxilaprevir in Treatment-Naïve and Treatment-Experienced Genotype 1-6 Chronic HCV-Infected Patients
Gilead Sciences, Inc. (NASDAQ: GILD) today announced topline results from four international Phase 3 clinical studies (POLARIS-1, POLARIS-2, POLARIS-3 and POLARIS-4) evaluating an investigational, once-daily, fixed-dose combination of sofosbuvir (SOF), a nucleotide analog NS5B polymerase inhibitor; velpatasvir (VEL), a pangenotypic NS5A inhibitor; and voxilaprevir (VOX; GS-9857), an investigational pangenotypic NS3/4A protease inhibitor, for the treatment of genotype 1-6 chronic hepatitis C virus (HCV) infection.                      

From The Journals

Journal of Hepatology 2017 Issue
Summary @ MD
Dec 16, 2016
Hepatitis C Still Increases Mortality Rate After Being Cured

NATAP - Full Text Article
Mortality in hepatitis C patients who achieve a sustained viral response compared to the general population

Of Interest
Correspondence: Prof. Dr. J.K. Rockstroh
2016/2017 - New HCV two and three drug regimens on their way: what do they promise?
Topic Summary
Risk of HBV reactivation after starting DAA therapy
Surveillance for hepatocellular carcinoma (HCC) and risk for HCC after achieving SVR following DAA therapy.
Intravenous drug users and patients on opioid substitution therapy
Patients in the prison setting
HIV/HCV coinfected patients
Patients with renal insufficiency or on hemodialysis
Patients older than 70 years
Patients receiving short treatment durations of 8 week
HCV three drug rescue combinations with licensed drugs
New dual DAA combinations
New three drug combinations

The Lancet Gastroenterology & Hepatology
Dec 12, 2016
Editorial Access to HCV treatments: hurdles not barriers

Infectious Diseases and Therapy
Evidence shows value of treating all stages of chronic HCV
November 1, 2016
Available evidence suggests that HCV treatment with the new direct-acting antivirals (DAAs) should not be limited to patients with advanced liver disease.

Liver Cancer After Treatment For Hepatitis C
November 23, 2016
A collection of 2016 articles retrieved online from press releases, conferences (The Liver Meeting® 2016 and the International Liver Congress 2016) and peer-reviewed journals featuring long-term risk for liver cancer in those who were cured of Hepatitis C.

December 2016

The following article appeared in the December print edition of HCV NEXT, published online at Healio; Screening for HCC in the Post-SVR12 Setting

Gastroenterology & Hepatology
December 2016
Interview
The Possible Association Between DAA Treatment for HCV Infection and HCC Recurrence
Download the PDF
G&H  How common is the coexistence of hepatocellular carcinoma and hepatitis C virus infection in a patient?

RB  Among patients with hepatitis C virus (HCV) infection and cirrhosis, the risk of hepatocellular carcinoma (HCC) is estimated to be 1% to 3% per year. Thus, in any given year, the risk is relatively low, but over a decade, the risk is considerable. More importantly, with the rise in the number of baby boomers who have had HCV infection for more than 2 decades, we are seeing an increasing prevalence of HCC. Although the rate of new cases of HCV infection is falling, the prevalence of HCV infection with cirrhosis is still rising, as is the number of patients who have HCV infection and HCC.
Continue reading...

Research Article

November 25, 2016
What’s Important to the Patient? Informational Needs of Patients Making Decisions About Hepatitis C Treatment
Patients contemplating hepatitis C virus treatment want a great deal of information to make informed treatment decisions.

Journal Of Gastroenterology and Hepatology
November 2016
Comparative Treatment Effectiveness of Direct Acting Antiviral Regimens for Hepatitis C:  Data from the Veterans Administration
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/jgh.13652

Journal Of Hepatology

New Perspectives in HCV Infection
October 2016 Issue
Second generation direct-acting antivirals – Do we expect major improvements?
Future landscape of hepatitis C research – Basic, translational and clinical perspectives

Liver International
October 2016
The value of cure associated with treating treatment- naïve chronic hepatitis C genotype 1: Are the new all- oral regimens good value to society?

Gastroenterology
October 1, 2016
Hepatitis C Therapy: Game Over!
Alessio Aghemo, Maria Buti
DOI: http://dx.doi.org/10.1053/j.gastro.2016.09.034
Publication stage: In Press Accepted Manuscript
NS5B polymerase inhibitor sofosbuvir, NS5A inhibitor velpatasvir, and the new protease inhibitor GS-9857 (voxilaprevir)
Download PDF

Hepatology
Emerging complexities with HCV DAA regimens: Less is still way more.
September 2016
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/hep.28832

Clinical Gastroenterology and Hepatology

SVR Linked to Long-Term Reduction in Fibrosis, Cirrhosis
July Issue 2016

Serum Biomarkers Indicate Long-term Reduction in Liver Fibrosis in Patients With Sustained Virological Response to Treatment for HCV Infection

Journal of Viral Hepatitis
August 2016
GS-9857 in Patients With Chronic Hepatitis C Virus Genotype 1–4 Infection

Gastroenterology & Endoscopy News

The Changing HCV Landscape:
October 26, 2016
Hepatitis C virus (HCV) continues to be a significant global burden, with more than 170 million people...

Conferences, Learning Activities and Guidelines

International Congress on Drug Therapy in HIV Infection

Generic hepatitis C drugs purchased online achieve high cure rates
October 27, 2016
Use of generic versions of direct-acting antivirals resulted in very high cure rates for people who obtained the products through three buyers’ clubs, indicating that the generic products are effective, according to three presentations at the International Congress on Drug Therapy in HIV Infection (HIV Glasgow) this week.

Of Interest
AASLD 2016: Generic Sofosbuvir Underperforms in Real World, May Be Due to Suboptimal Regimens

Dec 15, 2016

Generic sofosbuvir-based combinations for hepatitis C may not perform as well as branded sofosbuvir-containing regimens, according to a study conducted in Qatar and presented at the recent 2016 AASLD Liver Meeting. People treated with generics were less likely to be cured and more likely to experience adverse events compared to people who received branded drugs. But the investigators speculate that the generics may have underperformed because many people treated were with suboptimal regimens, and believe this deserves further research.

Watch - An Introduction to Access to Generic Hepatitis C Medicines
November 8, 2016
Following the success of the first two webinars in the Knowledge for Change series covering access to diagnostics and medicines, we were pleased to deliver the next in the series, ‘An Introduction to Accessing Generic Hepatitis C Medicines’ on 1 November. The webinar explored the generics landscape for hepatitis C with discussions on legalities, quality and performance of generics medicines as well as providing examples of how people across the globe are accessing them.

EASL- AASLD Special Conference New perspectives in hepatitis C virus infection - The roadmap for cure
September 23, 2016
Watch Summary Presentation - EASL Recommendations on Treatment of Hepatitis C 2016

EASL Recommendations on Treatment of Hepatitis C
Download 2016 - Update of the HCV EASL recommendations

American Association for the Study of Liver Diseases 67th Annual Meeting 2016

AASLD 2016 Review - Watch Advances in Chronic Hepatitis C: Management and Treatment

November 18, 2016

After each conference this blog links to a series of education-related information on important findings related to ongoing challenges of managing and treating viral hepatitis. Review three programs offering a review of key studies presented at the American Association for the Study of Liver Diseases 67th Annual Meeting 2016.

New at Healio
December 26, 2016

The Take Home - The Liver Meeting 2016
Infectious Disease Week 2016
The Liver Meeting 2016: Beyond HCV

Related
Healio - Highlights from The Liver Meeting

AASLD Coverage @ HIV and Hepatitis

ALL CONFERENCE COVERAGE
HIV and Hepatitis

VIDEO: Cost to treat HCV could be as low as $80 in the US
November 19, 2016
In this exclusive video at The Liver Meeting, Andrew M. Hill, PhD, discusses data from a new study that show the price of a direct-acting antiviral generic regimen could be as low as $80 in the U.S. to cure hepatitis C virus infection in one patient.

American College of Gastroenterology (ACG) 2016 Annual Scientific Meeting

Hep C Treatment Prognosis Continues to Amaze

November 22, 2016

LAS VEGAS — Rapid advances in the treatment of hepatitis C have clinicians seeing outcomes they never thought possible, and experts are optimistic that more complex and challenging patients will respond to therapy.

Healio

See more from American College of Gastroenterology Annual Meeting

National AIDS Treatment Advocacy Project (NATAP)

View All 2016 HCV and HIV conference reports at NATAP

2016 Updates

HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C

HCV Guidelines Update: People with HCV Should Be Tested for HBV Before Starting Antiviral Therapies
September 16, 2016
All patients beginning hepatitis C (HCV) treatment using direct acting antiviral (DAA) therapies should be assessed for hepatitis B (HBV), according the American Association for the Study of Liver Diseases/Infectious Diseases Society of America Guidance Panel, which provides up-to-date guidance on the treatment of hepatitis C on its website, HCVguidelines.org.

AASLD Offers Two New Practice Guidelines
New Practice Guidelines covering the treatment of hepatocellular carcinoma and portal hypertensive bleeding in cirrhosis have been released by AASLD.

These evidence-based guidelines are developed and updated regularly by a committee of experts and include recommendations of preferred approaches to the diagnostic, therapeutic, and preventative aspects of care.

Portal hypertensive bleeding in cirrhosis: Risk stratification, diagnosis, and management was published in December. Treatment of Hepatocellular Carcinoma has a January 2017 publication date.

For details about AASLD’s practice guidelines, click here.

FDA MedWatch/Direct-Acting Antivirals for Hepatitis C: Drug Safety Communication - Risk of Hepatitis B Reactivating
October 4, 2016

The FDA is warning about the risk of hepatitis B virus (HBV) becoming an active infection again in any patient who has a current or previous infection with HBV and is treated with certain direct-acting antiviral (DAA) medicines for hepatitis C virus. In a few cases, HBV reactivation in patients treated with DAA medicines resulted in serious liver problems or death. HBV reactivation usually occurred within 4-8 weeks.

July 6, 2016

This version of the Guidance has been updated to reflect several important developments, including the recent approval of sofosbuvir/velpatasvir, together with new information regarding the use of testing for HCV resistance associated variants....
Read more 

February 24, 2016

This version of the Guidance has been updated to reflect several important developments, including the recent approval of elbasvir/grazoprevir, together with new information regarding the use of testing for HCV resistance associated variants....
Read more 

Emerging Hepatitis C Treatment Strategies For Difficult‐to‐Cure Patients
November 12, 2016
Sit back and watch a panel of HCV experts discuss the recent updates and changes to AASLD-IDSA recommendations for testing, managing, and treating hepatitis C. Other topics include: efficacy of various DAA regimens in patients who have failed prior DAA therapies and efficacy and safety of different DAA regimens in the new difficult-to-cure patients.

Top Hepatitis Stories From Around The Web

Healio
HCV Next Cover Story - 2017 A Year in Transition
2017: A Year in Transition
"HCV Next" features cutting edge news on the latest HCV research developments. With in-depth articles on a range of topics; diagnosis, hepatitis c treatment regimens, side effects, drug/drug interaction, guidelines, practice management issues, to name a few.
Begin here.....

HIVandHepatitis.com 
Top 10 HIV and Hepatitis Stories of 2016

Simplification and optimization of antiretroviral therapy for HIV, wider use of pre-exposure prophylaxis (PrEP), a growing appreciation that people with undetectable viral load do not transmit HIV, and an expanded armamentarium of treatments for hepatitis C were among the top HIV and viral hepatitis headlines this year. Here's a look back at some of our biggest news from 2016.

Hepatitis B Foundation

Ten Things You Should Know About Hepatitis B and Do in 2017
It’s 2017, and experts around the world continue to study the complex life cycle of the hepatitis B virus in order to find a chink in its armor that will lead to a cure. In 2016, there were successes and disappointments in the research and healthcare arena. Here is what you need to know about hepatitis B in 2017.

Healio: Top Ten Most Read Articles In 2016
ILC coverage, HCV guidelines, FDA approvals among 2016 hot topics in hepatology

New data presented at the 2016 International Liver Congress, new guidelines on the management of hepatitis C virus infection from EASL and the WHO, and several new FDA approvals were among the most popular news topics covered by Healio.com/Hepatology this year.

HEP Your Guide To Hepatitis

Here are the stories and blogs with the most shares across social media this year;
2016 Top Shared Stories

1. FDA Approves Gilead’s Hepatitis C Regimen Epclusa (Sofosbuvir/Velpatasvir)
Posted: June 28

2. Epclusa: The Newest Hepatitis C Treatment
Posted: June 28

3. Looks Like Boomers Didn’t Get Hepatitis C From Youthful Drug Use After All
Posted: April 13

4. Hepatitis C Is Now the Biggest Killer Among All Infectious Diseases
Posted: May 4

5. Success for 8 Weeks of Gilead’s All-Genotype Hepatitis C Regimen
Posted: April 25

6. Zepatier: The Newest Hepatitis C Drug
Posted: February 1

7. After Curing Hepatitis C, Risk of Liver Cancer Remains Elevated
Posted: June 15

8. All Veterans With Hepatitis C, Without Restrictions, to Get Treatment
Posted: March 15

9. Near Perfect Hepatitis C Cure Rate For Ravidasvir and Sovaldi Among Those With Genotype 4
Posted: March 6

10. Hepatitis C is Killing Americans in Record Numbers While Patients Cannot Access Life Saving Medicine
Posted: May 16

11. Harvoni is Safe and Effective in Seniors With Hepatitis C
Posted: March 30

12. Hep C Relapses Are Uncommon Among Those Proclaimed Cured, But Reinfection is a Concern
Posted: March 7

13. Tattoos and Hepatitis C: What Are the Risks?
Posted: July 14

14. How Long Does Recovery From Hep C Treatment Take?
Posted: July 13

15. Hepatitis C Treatment Side Effects
Posted: May 31

Specialty Pharmacy Times
Lauren Santye, Assistant Editor
Publish Date: Wednesday, December 28, 2016
AbbVie Hepatitis C Drug Granted Breakthrough Therapy Designation
Experimental hepatitis C medication treats genotypes 1 through 6.

A Patient's Long, Difficult Journey to a Cure for Hepatitis C

Burdened by the symptoms of hepatitis C, an Australian man faced an uncertain future before new antiviral drugs offered hope.

Zepatier Tops Other Hepatitis C Drugs in Safety Comparison

Researchers compare top selling hep C medications Zepatier, Sovaldi, Harvoni, and Viekira Pak.

Merck Wins Nearly $2.5 Billion from Gilead in Hepatitis C Drug Royalties Verdict

Jury declares Merck’s acquired HCV drug patent valid.

First Drug for All Major Hepatitis C Genotypes Approved by FDA

Epclusa showed up to 99% viral suppression after 12 weeks across major hepatitis C genotypes.

Experts Call for End of Restricted Access to Hepatitis C Antivirals for Drug Users

Achieving global elimination of the virus starts with illicit drug users accessing curative hepatitis C virus treatments.

Is Prior Authorization Creating a Barrier to Eradicating Hepatitis C?

Nearly 1 of 4 initial requests for Harvoni were denied in a recent study of hepatitis C drug coverage.

Pharmacist Pleads Guilty in Hepatitis C Drug Fraud Case

Tennessee pharmacist admits to falsifying prior authorizations, medical lab reports, and drug test results for at least 51 hepatitis C patients prescribed Sovaldi, Harvoni, Viekira Pak, and Daklinza.

Black Plague Left Clues for Fighting Hepatitis C, HIV

Aberrant protein mutation associated with the black plague may lead to treatments for HIV and hepatitis C.

Improved Hepatitis C Screening Still Needed for Baby Boomers

Baby boomer generation are five times more likely to be diagnosed with hepatitis C virus.

Most Physicians Believe High-Cost Hepatitis C Drugs Are Worth the Price Tag

Debate continues surrounding cost versus cure in hepatitis C treatment.

Express Scripts Adds Hepatitis C Drug Harvoni to 2017 National Formulary

After 2 years of exclusion, Harvoni has been added to the Express Scripts national formulary for the treatment of hepatitis C.

New Hepatitis C Drug Expected to Challenge Dominance of Gilead in HCV Market

Zepatier is priced considerably lower with similar efficacy to Harvoni and Sovaldi.

As Out-of-Pocket Costs Rise, Hepatitis C Drug Adherence Drops

Manufacturer coupons found to show significant benefits reducing Sovaldi cost share.

GoodRx
2016 Year in Review: Good News, Bad News, and Looking Ahead to 2017
The two largest prescription insurance companies, Express Scripts and Caremark, dropped coverage for 40 popular drugs in 2016. Most notably, medications like the popular insulin Lantus, and venlafaxine ER (Effexor XR) for depression have been dropped by Caremark. Express Scripts dropped Taltz for psoriasis, and Orencia for rheumatoid arthritis, among others, and Viekira Pak now has only limited coverage. Insurers are also restricting coverage for many of the expensive (but effective) hepatitis C drugs like Zepatier and Olysio, leaving only Sovaldi and Harvoni as options.

                          

Wishing you all a safe and healthy 2017!
Tina