Spontaneous Clearance of HCV Infection in Patients with Chronic Infection

NEJM Journal Watch

July 28, 2016
Spontaneous Clearance of HCV Infection in Patients with Chronic Infection

Atif Zaman, MD, MPH reviewing Bulteel N et al. J Hepatol 2016 Aug.

Atif Zaman, MD, MPH
Factors associated with this rare event were younger age, female gender, HBV coinfection, and lower HCV RNA level.

Atif Zaman, MD, MPH
The incidence of spontaneous clearance of hepatic C virus (HCV) infection in the acute phase (infected <6 months) is high (estimated at 20%–40%) but is unknown in the chronic phase.

In a population-based case-control study performed in Scotland, investigators assessed spontaneous clearance incidence and its associated risk factors, using HCV testing data from 1994 to 2013. Case patients were defined as those who spontaneously resolved HCV infection and control patients as those who remained chronically infected. All patients had no prior HCV treatment and had ≥2 sequentially positive HCV RNA tests at least 6 months apart, followed by ≥2 negative tests in cases and no negative tests in controls. Four controls were randomly selected for each case.

Among 10,318 patients identified with positive hepatitis B virus (HBV) RNA samples, 50 had documented late spontaneous clearance, for an incidence of 0.36 per 100 person-years of follow-up. Median duration of infection was 50 months in both cases and controls. Spontaneous clearance was significantly associated with younger age at infection (median age, 29 vs. 33 years), female gender, co-infection with HBV infection, and lower HCV RNA level.

Comment
These data demonstrate that spontaneous clearance of HCV infection can occur in patients who are chronically infected, albeit at an extremely low rate. Although the exact mechanism of this late spontaneous clearance is unknown, as seen here, certain host and viral factors appear to play a role. On rare occasion, clinicians may see this occur in practice.

Editor Disclosures at Time of Publication
Disclosures for Atif Zaman, MD, MPH at time of publication Nothing to disclose

Citation(s):
Bulteel N et al. Factors associated with spontaneous clearance of chronic hepatitis C virus infection. J Hepatol 2016 Aug; 65:266. (http://dx.doi.org/10.1016/j.jhep.2016.04.030)

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New at NEJM Journal Watch

Gastroenterology Common Reasons for Hospital Readmissions in Patients with Cirrhosis
Atif Zaman, MD, MPH reviewing Tapper EB et al. Clin Gastroenterol Hepatol 2016 Aug.
Top readmission causes were acute complications of cirrhosis, substance abuse, and cancer complications.

Efficacy of Sofosbuvir, Velpatasvir, and GS-9857 Genotype 1, 2,3,4 or 6 / Phase 2 Trial

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Source: Gastroenterology

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Efficacy of Sofosbuvir, Velpatasvir, and GS-9857 in Patients with HCV Genotype 2, 3, 4, or 6 Infections in an Open-label, Phase 2 Trial
Edward Gane, Kris V. Kowdley, David Pound, Catherine A.M. Stedman, Mitchell Davis, Kyle Etzkorn, Stuart C. Gordon, David Bernstein, Gregory Everson, Maribel Rodriguez-Torres, Naoky Tsai, Omer Khalid, Jenny C. Yang, Sophia Lu, Hadas Dvory-Sobol, Luisa M. Stamm, Diana M. Brainard, John G. McHutchison, Myron Tong, Raymond T. Chung, Kimberly Beavers, John E. Poulos, Paul Y. Kwo, Mindie H. Nguyen
DOI: http://dx.doi.org/10.1053/j.gastro.2016.07.038
Publication stage: In Press Accepted Manuscript

Published online: July 30, 2016

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Studies are needed to determine the optimal regimen for patients with chronic hepatitis C virus (HCV) genotype 2, 3, 4, or 6 infections who have failed by a prior course of antiviral therapy, and the feasibility of further shortening treatment duration. We performed a phase 2 study to determine the efficacy and safety of the combination of the nucleotide polymerase inhibitor sofosbuvir, the NS5A inhibitor velpatasvir, and the NS3/4A protease inhibitor GS-9857 in these patients.

DISCUSSION ONLY
With the recent approval of DAAs, safe and effective combination regimens are now available for the majority of patients chronically infected with HCV. SVR rates exceeding 90% can be achieved in most patient populations regardless of genotype, treatment experience, or presence of cirrhosis. Although the proportion of patients who do not achieve SVR with currently approved DAA regimens is small, the absolute number of DAA failures will steadily increase in parallel with the rate of treatment uptake. DAA failures represent an unmet medical need without, at this time, any approved retreatment options. In this open-label, phase 2 study, the combination of sofosbuvir velpatasvir plus GS-9857 for 12 weeks was safe and highly effective for the treatment of patients with genotypes 2, 3, 4, or 6 HCV infection with or without compensated cirrhosis who were treatment-experienced, including those who had failed previous DAA regimens. The high SVR12 rate among treatment-experienced patients with genotype 3 HCV infection and cirrhosis is noteworthy, given the lower SVR12 rates generally experienced by patients this patient population.

Currently approved regimens for non-genotype 1 HCV have durations of 12 to 24 weeks, depending on choice of regimen and patient’s baseline characteristics, such as HCV genotype, treatment history and presence or absence of cirrhosis. The feasibility of further shortening the duration of treatment has been a goal of research, especially for non-ribavirin containing regimens. Several trials have evaluated various combinations of DAAs for four weeks, but with uniformly disappointing 0utcomes—SVR12 rates of 20% to 40%

In this trial, 6 weeks of sofosbuvir-velpatasvir plus GS-9857 achieved suboptimal results (<90% SVR12 rate) in a historically easy-to-treat population of treatment-naïve patients without cirrhosis. Eight weeks of sofosbuvir-velpatasvir plus GS-9857 was safe and effective for treatment-naïve patients with cirrhosis, including those with HCV genotype 3. Thus, the 8-week regimen may serve as a shorter-duration option for treatment-naïve patients with or without cirrhosis and is currently being evaluated in Phase 3 clinical trials.

Additionally, the high SVR12 rates across genotypes suggests the pangenotypic treatment potential of sofosbuvir-velpatasvir plus GS-9857. While genotype 1 patients were not treated in this study, a parallel open-label, phase 2 study of patients infected with HCV genotype 1 was also conducted,where patients received treatment for 6 to 12 weeks.

This study was limited by its small sample size and open-label design. Although the first Phase 2 clinical trial to evaluate retreatment of non-genotype 1 HCV infected patients previously treated with DAA-regimens that included NS5A inhibitors, only six patients in this subgroup were enrolled. Also, no patients with genotype 5 HCV and only 3 patients with genotype 6 HCV were enrolled, reflecting the low prevalence of these infections in North America and New Zealand.

In conclusion, sofosbuvir-velpatasvir plus GS-9857 is a safe and effective treatment in patients with HCV genotypes 2, 3, 4, and 6, with and without compensated cirrhosis. High SVR rates were achieved in treatment-experienced patients, including those with DAA-experience, after12 weeks of sofosbuvir-velpatasvir plus GS-9857 and in treatment-naïve patients with compensated cirrhosis after 8 weeks of this regimen. These three potent pangenotypic DAAs have been coformulated into afixed-dose combination tablet. The Phase 3 program will evaluate this fixed-dose combination in patients for eight weeks treatment-naïve patients of all genotypes and for twelve weeks in patients of all genotypes who had received previous treatment with a DAA.

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Efficacy of Sofosbuvir, Velpatasvir, and GS-9857 in Patients with Genotype 1 Hepatitis C Virus Infection in an Open-label, Phase 2 Trial
Eric Lawitz, Nancy Reau, Federico Hinestrosa, Mordechai Rabinovitz, Eugene Schiff, Aasim Sheikh, Ziad Younes, Robert Herring Jr., K. Rajender Reddy, Tram Tran, Michael Bennett, Ronald Nahass, Jenny C. Yang, Sophia Lu, Hadas Dvory-Sobol, Luisa M. Stamm, Diana M. Brainard, John G. McHutchison, Brian Pearlman, Mitchell Shiffman, Trevor Hawkins, Michael Curry, Ira Jacobson
DOI: http://dx.doi.org/10.1053/j.gastro.2016.07.039
Publication stage: In Press Accepted Manuscript

The best regimen to retreat patients who do not respond to direct-acting antivirals (DAAs) and the feasibility of further shortening regimens is unclear. We assessed the efficacy and safety of the combination of the nucleotide polymerase inhibitor sofosbuvir, the NS5A inhibitor velpatasvir, and the NS3/4A protease inhibitor GS-9857 in patients with hepatitis C virus (HCV) genotype 1 infection.

Published online: July 30, 2016

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DISCUSSION ONLY
The development of oral DAAs represents a major advance in the treatment of HCV in patients of all genotypes. Currently available DAA combination regimens offer SVR rates well over 90% overall and in most patient subpopulations. Nevertheless, some patients do not achieve SVR with existing regimens. Patients who have failed prior treatment with first generation NS3/4A protease inhibitors (e.g., telaprevir, boceprevir, or simeprevir) may be retreated with ledipasvir sofosbuvir, but patients who have been unsuccessfully treated with a regimen that includes an NS5A inhibitor have no approved retreatment options. In a previous trial, patients with genotype 1 HCV who did not achieve SVR after 8 or 12 weeks of ledipasvir-sofosbuvir-based regimens and were subsequently retreated with 24 weeks of ledipasvir-sofosbuvir had an SVR12 rate of only 71%. In this population, the presence of baseline NS5A RASs was associated with a higher rate of virologic failure (Lawitz et al: J Hepatol 62:S192 Abstract, 2015).

In another small trial, 14 of 16 patients (88%) who had previously failed a daclatasvir-containing regimen achieved SVR12 after retreatment with simeprevir-sofosbuvir for 12 weeks. Thirteen of the 16 patients had NS5A RASs at baseline, and of these 13, 11 (85%) achieved SVR12. The 2 patients who did not achieve SVR12 had Q30K and L31M substitutions as the dominant viral populations at retreatment baseline.16

In this open-label, phase 2 study, 12 weeks of treatment with sofosbuvir-velpatasvir plus GS9857 was safe and highly effective in patients with HCV genotype 1, with and without cirrhosis, who did not achieve SVR after prior treatment with DAA, including those who had previously received an NS5A inhibitor. In treatment-naive patients, the 8-week regimen was safe and effective, regardless of cirrhosis status. Among the treatment-naïve patients who relapsed, the presence of baseline RASs appeared to have no impact on treatment outcome. Treatment emergent RASs by deep sequencing with a 1% cutoff were rare (3/17, 18%) and no treatment emergent RASs among relapsers were detected with the 15% cutoff. This is consistent with the anticipated high barrier of resistance of the combination therapy based on in vitro data (Lawitz et al: Hepatology XXX Abstract 2015).

Treatment-naïve patients without cirrhosis treated for 8 weeks achieved a SVR12 rate of 100%,which is higher than results reported in other recent studies of combining 3 or 4 DAAs for treatment for the same population and treatment duration.20,21 Treatment-naïve patients with cirrhosis treated for 8 weeks had lower SVR12 rates of 81-94% than patients without cirrhosis. Larger studies will determine whether this short duration is adequate for this patient population. One unexpected result in our trial was the apparent lack of benefit of the addition of ribavirin to sofosbuvir-velpatasvir plus GS-9857 for treatment-naïve patients with cirrhosis. Although patients in this group receiving ribavirin had a numerically lower rate of SVR12 than treatment naïve patients with cirrhosis who received sofosbuvir-velpatasvir plus GS-9857 without ribavirin (81% vs 94%), the confidence intervals overlap and it is likely that this reflects the small sample sizes. 

Factors limiting the interpretation of these results of this trial include its small size and uncontrolled, open-label design. Although the trial enrolled only patients with genotype 1 HCV, another trial of similar design has been conducted to assess this combination regimen in patients with non-genotype 1 HCV.

In conclusion, sofosbuvir-velpatasvir plus GS-9857 for 12 weeks provided a high rate of SVR12 (100%) and was well-tolerated in a group of patients currently without treatment options—those with and without compensated cirrhosis who have not achieved SVR after previous treatment with a NS5A inhibitor-containing regimen. The addition of GS-9857 to sofosbuvir-velpatasvir was also safe in the treatment-naïve population where it was effective in reducing the treatment duration to 8 weeks while preserving a high rate of SVR12. These three potent pangenotypic DAAs have been coformulated into a fixed-dose combination tablet. The Phase 3 program will evaluate this fixed-dose combination for eight weeks in treatment-naïve patients and for twelve weeks in DAA-experienced patients, including those who have previously received an NS5A inhibitor.

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Shire’s SHP626 (Volixibat) Receives FDA Fast Track for Adults who have NASH with Liver Fibrosis

Shire’s SHP626 (Volixibat) Receives FDA Fast Track Designation for an Investigational Treatment for Adults who have Nonalcoholic Steatohepatitis (NASH) with Liver Fibrosis

July 29, 2016

Lexington, Mass. – July 29, 2016 – Shire plc (LSE: SHP, NASDAQ: SHPG) today announced that the United States Food and Drug Administration (FDA) has granted Fast Track designation for SHP626 (volixibat) for an investigational treatment of adults who have nonalcoholic steatohepatitis (NASH) with liver fibrosis. Shire is developing SHP626 as a once daily, orally-administered inhibitor of the apical sodium dependent bile acid transporter (ASBT), a protein which is primarily responsible for recycling bile acids from the intestine to the liver. NASH is a serious, chronic liver disease for which there are currently no approved drugs.

"Shire’s development plan for SHP626 is designed to address the unmet need in the treatment of adult patients who have NASH with liver fibrosis,” said Philip J. Vickers, Ph.D., Head of R&D, Shire. "This Fast Track designation is further recognition of the critical need to develop new, effective therapeutic options for patients with this serious condition." The FDA Fast Track Designation for SHP626 in NASH was supported by preclinical and Phase 1 studies. The FDA’s Fast Track is a process designed to facilitate the development, and expedite the review of drugs to treat serious conditions and fill an unmet medical need. However, it does not guarantee that the FDA will ultimately approve SHP626 for NASH or the timing of any such approval.

Shire will initiate its Phase 2 trial with SHP626 as a randomized, placebo-controlled, double-blind study to evaluate the safety, tolerability and efficacy of three doses of volixibat over 48-weeks in adult patients with NASH. The Phase 2 study will be conducted in the U.S., Canada and the United Kingdom.

Additional information on the SHP626 Phase 2 study can be found on clinicaltrials.gov: https://clinicaltrials.gov/ct2/show/NCT02787304?term=volixibat&rank=1

SHP626 has been evaluated in preclinical and Phase 1 studies, in which the safety, tolerability and preliminary activity of SHP626 compared to placebo in healthy volunteers, as well as in overweight and obese volunteers, was assessed. The most common adverse events occurring in Phase 1 trials of SHP626 were gastrointestinal in nature, predominantly diarrhea. While this occurred in most patients, it was not considered serious. There was one serious adverse event reported that was considered related to SHP626, alanine aminotransferase elevation, that led to discontinuation of drug.

About Nonalcoholic Steatohepatitis (NASH)

NASH is a type of nonalcoholic fatty liver disease (NAFLD), characterized by inflammation and the accumulation of fat in the liver, for which there are currently no approved drugs. It can be severe and lead to fibrosis, cirrhosis, liver failure and liver cancer. There is a steady rise in the prevalence of NASH in the U.S. and globally, and the disease is typically associated with obesity, type 2 diabetes, hypertension, high cholesterol and triglycerides. NASH is currently the second leading cause of liver transplantation in adults in the U.S., and is estimated to become the leading cause for liver transplantation if the current trajectory continues.

https://www.shire.com/newsroom/2016/july/7zve23

Dr. Yasmin Thanavala on targeted therapy for liver cancer

Roswell Park Findings Will Help Clinicians Select Best Therapy for Patients with Advanced Liver Cancer

Newswise — BUFFALO, NY - New research from Roswell Park Cancer Institute offers clinicians treating patients with advanced liver cancer a way of determining which patients may benefit most from the targeted therapy sorafenib.

“Our study is the first to demonstrate the potent immunotherapeutic benefits of sorafenib and to suggest that this targeted treatment may extend survival among a subset of patients with liver cancer,” says the paper’s senior author, Yasmin Thanavala, PhD, Professor in the Department of Immunology and Member of the Tumor Immunology and Immunotherapy program at Roswell Park. “The drug has significant antiangiogenic properties, and also appears to beneficially impact the suppressed immune system of patients with advanced liver cancer.”

Looking at blood samples from patients with advanced liver cancer, researchers evaluated the frequency and expression levels of several immunosuppressive cells and molecules before and after treatment with sorafenib. The team found a statistically significant reduction of the checkpoint molecule PD-1 and levels of its expression on important immune cells known as “helper,” “killer” and regulatory T cells, and that this response was strongly linked to the patients’ overall survival. They also observed a beneficial increase in the ratio of T effector cells to T regulatory cells following treatment with sorafenib. The findings suggest that sorafenib reduces the number of immune-suppressing cells in patients who respond to therapy, and that the combination of this targeted agent with immune-based therapies may improve treatment outcomes in patients with liver cancer.

“These results indicate that patients with an increased number of cells expressing the checkpoint molecule PD-1 before treatment are more responsive to sorafenib therapy. These increased numbers in pretreatment blood samples may be a biomarker indicating which patients will respond better to therapy and may help to predict overall patient survival,” adds Dr. Thanavala.

This research has been highlighted in a press release from the journal JCI Insight.

Editor’s note: See a video interview with Dr. Yasmin Thanavala, lead author of the study, at https://youtu.be/X3H_avWi-Ko

Wider access to hepatitis C drugs is humane and pragmatic

Wider access to hepatitis C drugs is humane and pragmatic
 Boston Globe

The long-term health prospects for thousands of Massachusetts residents are about to improve. As of Monday, MassHealth will require private insurers that manage coverage for two-thirds of the state Medicaid plan’s members to loosen rules that cruelly prevent people infected with hepatitis C from receiving drugs that cure the disease. Until now, these low-income patients have been forced to wait until they are suffering from potentially deadly symptoms before getting a prescription for one of a new generation of medicines that kills the liver-ravaging virus in as little as eight weeks.

The insurance company restrictions were a misguided reaction to the cost of the breakthrough treatments for hepatitis C, a disease which previously could only be kept in check — but not cured — by drugs that came with terrible side effects. When Gilead Sciences Inc.’s Sovaldi became the first of the more effective medicines to hit the market, in 2013, its $84,000 list price — $1,000 a pill — caused sticker shock for payers nationwide. Fearing their budgets would be drained by a rush of people who wanted to get well instead of living with uncertainty, many insurers limited access to Sovaldi. Even from a cold-blooded accountant’s perspective, it was a foolish policy — providing months or years of medical care for someone suffering from cirrhosis costs much more.

Continue reading.....

David Bernstein: Managing Risk Factors in Hepatitis C

David Bernstein: Managing Risk Factors in Hepatitis C
Jul 27, 2016 | Adam Hochron

Article available @ MD Magazine   

Watch:

David Bernstein: Charting a Course Toward Liver Transplantation
David Bernstein from Northwell Health: Hepatitis C Now a Largely Treatable Condition
View all videos .... http://www.hcplive.com/videos

David Bernstein: Managing Risk Factors in Hepatitis C

MD Magazine TV
Now that most forms of hepatitis C are treatable if not curable other conditions like fatty liver disease are drawing a lot of attention in the field of hepatology.

UK health service under fire over access to hepatitis C drugs

Feature Investigation
A pill too hard to swallow: how the NHS is limiting access to high priced drugs
(Published 27 July 2016) Cite this as: BMJ 2016;354:i4117

A joint investigation by The BMJ and Cambridge and Bath universities uncovers how NHS England tried to limit access to expensive new drugs for hepatitis C.
Jonathan Gornall, Amanda Hoey, and Piotr Ozieranski report

Highly priced medicines are challenging health systems around the world in unprecedented ways. And none more so than the new sofosbuvir based antiviral drugs introduced by Gilead Sciences in 2014. Offering greatly reduced treatment durations and high cure rates, these medicines hold out the real prospect of eliminating hepatitis C in countries where they are widely administered, with all that implies for long term savings in healthcare costs.

Continue reading...

England's NHS waged a tense behind-the-scenes fight against pricey hep C drugs
by Tracy Staton
When England’s cost-effectiveness gatekeepers gave their blessing to Gilead Sciences’ pricey hepatitis C drugs last year, some of the country’s sickest patients were already being treated under a special access program.

But as the National Institute for Health and Care Excellence (NICE) was weighing Gilead’s evidence and pricing on Sovaldi and Harvoni, the country’s National Health Service was maneuvering behind the scenes to delay or block the agency’s approvals, according to a BMJ investigation to be published Thursday.
Continue reading....

NHS England tried to sabotage hepatitis C drugs release because it couldn't afford them, doctors claim
Doctors from the clinical advisory group have claimed NHS England tried to sabotage attempts to introduce the expensive drugs, to delay them until the following financial year because they didn't have enough funding

Continue reading....

UK health service under fire over access to hepatitis C drugs

British health authorities improperly restrict access to expensive new hepatitis C drugs that can cure the liver-destroying disease, patient groups and a leading medical journal charged on Thursday.

Despite the clear benefits of the drugs, the National Health Service in England rations the drugs to just 10,000 people with the virus each year, campaigners said.

The Hepatitis C Trust said it was now seeking a judicial review of NHS England’s decision and the court is considering whether to grant permission for the case to go ahead.

Hepatitis C drugs have become the focus of a fierce debate over the high cost of modern medicines, after Gilead Sciences launched the first of the products, Sovaldi, with a U.S. price tag of $1,000 per pill.

In Britain, the National Institute for Health and Care Excellence (NICE), the cost-effectiveness watchdog, recommended the new drugs for the majority of hepatitis C patients, but the British Medical Journal said NHS England had defied NICE’s authority by rationing access.

NHS England said the journal's claims were inaccurate and hepatitis C was its single biggest new treatment investment in years, adding it was "naive" to think the system could pay for coverage for all patients at once.

"As prices come down due to more competition between drug companies, in future years we'll be able to expand hep C treatments even further within the funding available, and the industry is now engaging in discussions with us about how best to do this," a spokesperson said.

(Reporting by Ben Hirschler, editing by Larry King)

Source

New medication shows promise against liver fibrosis in animal studies

New medication shows promise against liver fibrosis in animal studies

A new drug developed by scientists at the National Institutes of Health limits the progression of liver fibrosis in mice, a hopeful advance against a condition for which there is no current treatment and that often leads to serious liver disease in people with chronic alcoholism and other common diseases.

“This study represents an important step towards an effective treatment for liver fibrosis.”

—George F. Koob, Ph.D., Director, NIAAA

“This study represents an important step towards an effective treatment for liver fibrosis,” said George F. Koob, Ph.D., director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA), part of NIH. A report of the study, led by NIAAA scientists, is now online in JCI Insight.

Liver fibrosis is a gradual scarring of the liver that puts people at risk for progressive liver disease and liver failure. It may develop as a late consequence of chronic alcoholism, viral hepatitis, obesity or diabetes and can progress to cirrhosis and liver cancer, yet currently there is no therapy approved by the U.S. Food and Drug Administration.

The new compound is a chemically modified version of ibipinapant, a brain-penetrating cannabinoid type 1 (CB-1) receptor antagonist used in scientific research. Senior author and NIAAA Scientific Director, Dr. George Kunos’ team modified its structure to reduce its ability to penetrate the brain, and to include a molecular group that directly inhibits iNOS, the enzyme responsible for generating nitrogen compounds that promote inflammation.

“Fibrosis is a multifactorial, complex disorder that can benefit from simultaneous targeting of more than one cellular process,” explained Dr. Kunos.

Dr. Kunos and his NIAAA team developed a new medication that concurrently inhibits both CB-1 receptors and iNOS. The new compound was designed to have only very limited ability to enter the brain in order to avoid the psychiatric side effects that limit the usefulness of currently available, brain-penetrant CB-1 receptor-blocking compounds.

“Inducible nitric oxide synthase, or iNOS, is an enzyme that has been shown to play a fundamental role in liver fibrosis pathology and is a potential target for fibrosis therapy,” said Dr. Kunos. “It is also an important factor in alcoholic liver disease, viral hepatitis, fatty liver disease, and other pathologies that promote liver fibrosis.”

Previous studies have also shown that endocannabinoids, natural messengers in the body that help regulate many biological functions, play a role in liver fibrosis and, current compounds that block CB-1 receptors in the liver are moderately effective against liver fibrosis in animal models of the disease. However, because such compounds penetrate the brain and also block CB-1 receptors in the brain, they have undesirable psychiatric effects.

In the current study, Dr. Kunos and his colleagues tested the compounds in two widely used mouse models of liver fibrosis unrelated to obesity. They found that the new compound was more effective in limiting fibrosis than compounds targeting either CB-1 receptors or iNOS alone.

Dr. Kunos notes that, in addition to the new compound’s decreased ability to cause psychiatric side effects, it has also passed preliminary screening tests for other possible side effects such as genotoxicity or interactions with other receptors or ion channels that could generate “off-target” effects. He adds, however, that the compound will require more extensive safety screening in animals before seeking FDA approval for studies of its therapeutic potential in humans. Dr. Kunos and his colleagues will collaborate with other researchers on such studies in the coming months.

The National Institute on Alcohol Abuse and Alcoholism, part of the National Institutes of Health, is the primary U.S. agency for conducting and supporting research on the causes, consequences, prevention, and treatment of alcohol abuse, alcoholism, and alcohol problems. NIAAA also disseminates research findings to general, professional, and academic audiences. Additional alcohol research information and publications are available at: https://www.niaaa.nih.gov.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

Adding ribavirin to newer DAA regimens does not affect SVR rates in HCV genotype 1 infected persons: results from ERCHIVES

Alimentary Pharmacology & Therapeutics

Early View (Online Version of Record published before inclusion in an issue)

Adding ribavirin to newer DAA regimens does not affect SVR rates in HCV genotype 1 infected persons: results from ERCHIVES

A. A. Butt^1,2,3,*, P. Yan¹, K. Marks³, O. S. Shaikh^1,4, K. E. Sherman⁵

Version of Record online: 26 JUL 2016

DOI: 10.1111/apt.13748

Background

Ribavirin is a key component of several hepatitis C virus (HCV) treatment regimens. However, its utility in combination with newer directly acting anti-viral agents regimens is unclear.

Aim
To determine the SVR rates with paritaprevir/ritonavir/ombitasvir/dasabuvir (PrOD) regimen ± ribavirin and compare this with sofosbuvir/simeprevir and sofosbuvir/ledipasvir regimens.

Methods
We used Electronically Retrieved Cohort of HCV Infected Veterans (ERCHIVES), a well-established national cohort of HCV-infected Veterans to identify HCV genotype 1 infected persons initiated on the above regimens. We excluded those with HIV coinfection, positive HBsAg and missing HCV RNA.

Results
We identified 1235 persons on PrOD (75.5% ribavirin), 1254 on sofosbuvir/simeprevir (16.9% ribavirin) and 4247 on sofosbuvir/ledipasvir (23.3% ribavirin). Among HCV genotype 1a infected persons, ribavirin was prescribed to 99.2% on PrOD, 18.2% on sofosbuvir/simeprevir and 23.3% on sofosbuvir/ledipasvir. The SVR rates ranged from 92.6% to 100% regardless of the treatment regimen, presence of cirrhosis or HCV subtype, except in PrOD group without ribavirin, HCV genotype 1a without cirrhosis (SVR 80%, N = 5). There were minor, clinically insignificant differences in SVR rates in those treated with or without ribavirin in each of the treatment groups, regardless of presence of cirrhosis at baseline. In multivariable logistic regression analysis, ribavirin use was not associated with achieving SVR in any group.

Conclusions
In HCV genotype 1 infected persons, PrOD, sofosbuvir/simeprevir and sofosbuvir/ledipasvir regimens, are associated with high rates of SVR in actual clinical settings, which are comparable to clinical trials results (except PrOD genotype 1a with cirrhosis where the number was too small). The benefit of adding ribavirin to these regimens in the ERCHIVES treated cohort is not established.

Discussion Only

Full Text Article Available @ Alimentary Pharmacology & Therapeutics

In this large national observational study of HCV infected persons in actual clinical settings, ribavirin use was not associated with any clinically meaningful differences in SVR rates among patients treated with newer DAA regimens. Presence of cirrhosis at baseline, HCV subtype and prior treatment status did not affect these results. Number of HCV genotype 1a infected persons treated with PrOD (without ribavirin) was too small to make any conclusions in this group (n = 6).

Our study demonstrates that treatment for HCV infection with newer oral regimens is associated with high SVR rates in actual clinical settings, and that these rates are comparable to those seen in clinical trials.[23] We have previously shown that treatment with sofosbuvir-based regimens in actual clinical settings is associated with SVR rates similar to clinical trials,[8] and this study provides similar assurance with PrOD regimen in similar settings. To our knowledge, this is among the first and largest study with data from actual clinical settings, that compares the three commonly used newer DAA agents.

Ribavirin was considered an important part of the treatment regimen with pegylated interferon and first generation DAAs. However, its role in all-oral regimens of newer DAAs is less clear. In one recent trial, virological failure was more common without ribavirin than with ribavirin among HCV genotype 1a infected patients but not among those with genotype 1b infection.[10] In another trial, ledipasvir + sofosbuvir + ribavirin for 12 weeks and ledipasvir + sofosbuvir without ribavirin for 24 weeks provided similar SVR12 rates in previous nonresponders with HCV genotype 1 and compensated cirrhosis.[24] Use of ribavirin is associated with significant haematological toxicity and drug–drug interactions, and it is a highly teratogenic agent.[25, 26] In a recent analysis of 1952 patients enrolled in phase III ION clinical trials, treatment-related adverse events were observed in 71% of patients treated with RBV, but in only 45% of patients treated without RBV.[26] While most adverse events were mild in severity and not associated with treatment discontinuation, there is some cost and risk to adding ribavirin to the regimen. Regimens without ribavirin are attractive in such settings.

The strongest and most consistent predictor of achieving SVR was duration of treatment. This is not surprising, and is consistent with numerous previous studies which have assessed patients treated in actual clinical settings.[8, 9] Future studies should assess the role of treatment adherence upon virological outcomes in these patients. Presence of cirrhosis at baseline was associated with a numerically large reduction in SVR rates (37% lower SVR rates for PrOD, 44% for sofosbuvir/simeprevir, 53% for sofosbuvir/ledipasvir), though this did not reach statistical significance in the PrOD group.

The newer treatment regimens remain associated with a low rate of adverse haematological adverse events.[27] Although anaemia was more common in those who received ribavirin, severe (grade 3/4) anaemia remains uncommon overall. In previous studies, we have shown that haematological parameters revert towards baseline after completion of treatment, providing some reassurance regarding the safety of these regimens.[9]

While our study provides new and important clinical information about newer DAA regimens derived from a well-established national database, there are certain limitations that need to be addressed when analysing administrative databases. The information in such databases is collected as part of routine clinical care, and is thus not always collected at rigorously defined time-points during the course of treatment. Given this is an observational study and not a randomized study of ribavirin use, confounding by indication is of concern. Persons who received ribavirin may have been harder to treat; however, in multivariate analysis controlling for these baseline predictors did not reveal a benefit of ribavirin use. Laboratory testing was performed at different laboratories, and subtle differences in results may affect overall results. Definition of cirrhosis was based on a non-invasive clinical marker (FIB-4 score), which was based on routine laboratory testing which may have been performed at different time-points prior to baseline. Number of persons in HCV genotype 1a PrOD group was too small (n = 6) to make any conclusions, and clinical trials data suggest that adding ribavirin in genotype 1a patients may be of some benefit.[10] We also did not analyse the role of resistance associated mutations upon virological response rates.

In conclusion, in HCV genotype 1 infected persons, PrOD, sofosbuvir/simeprevir and sofosbuvir/ledipasvir regimens are associated with high rates of SVR in actual clinical settings, which are comparable to those achieved in clinical trials (except PrOD genotype 1a with cirrhosis where number was too small). Addition of ribavirin to the regimen does not appear to enhance SVR rates in a clinically meaningful way, with the caveat that the number of persons in HCV genotype 1a PrOD group was too small to make any conclusions.

Continue reading....

1. Summary
2. Introduction
3. Methods
4. Results
5. Discussion
6. Authorship
7. Acknowledgements
8. References
9. Supporting Information
   
   

Discovery of new Hepatitis C Virus mechanism

Discovery of new Hepatitis C Virus mechanism

Osaka University

IMAGE: SPP inhibition reduces production of infectious HCV particles and pathogenesis, view more

Credit: Aizawa and Okamato et al. Nat Commun (2016)

Researchers at Osaka University, Japan uncovered the mechanisms that suppress the propagation of the hepatitis C virus (HCV) with the potential of improving pathological liver conditions. Using model mice, they confirmed that when a certain enzyme is inhibited, HCV particle production is reduced leading to an improvement of pathological liver conditions. They thereby identified a new drug target for the development of new HCV drugs.

About 200 million people around the world are infected with the HCV virus. HCV infection may cause fatty liver, hepatic fibrosis and liver cancer. In Japan, the HCV virus is the main cause for viral liver cancer, constituting 70% of liver cancers. Although the recent development of effective drugs targeting HCV replicative enzymes has enabled the elimination of HCV, challenges remain including the emergence of resistant viruses and the development of liver cancer after virus elimination. So far it was known that the cleavage of the HCV core protein by the enzyme signal-peptide peptidase (SPP) in infected host cells played an important role in the formation of viral particles and the development of pathological liver conditions. However, the details of this mechanism were not understood.

A research group led by Toru Okamoto, assistant professor and Yoshiharu Matsuura, professor at Research Institute for Microbial Diseases, Osaka University has now discovered that when the enzyme SPP is inhibited, HCV particle production is reduced resulting in an improvement of pathological liver conditions.

The researchers found a chemical compound that inhibits the SPP enzyme in the y-secretase inhibitor which is currently in the development process for Alzheimer's disease treatment. They also discovered that the immature core proteins which are not cleaved by SPP are recognized by the enzyme TRC8 and quickly degraded. If this degradation process is suppressed, cellular damage is strongly induced by endoplasmic reticulum stress (ER stress). The endoplasmic reticulum is central to protein biosynthesis and in a state of ER stress, the proteins synthesizing there are unable to fold up correctly thereby causing cell damage. This degradation process can therefore be considered as a quality control mechanism for new proteins. When the researchers administered the SPP inhibitor to model mice, HCV particle production was significantly reduced, improving HVC pathologic conditions such as insulin resistance and fatty liver.

The results of this study suggest the development of SPP inhibitors as a new hepatitis C drug. In addition, the observed protein quality control mechanism via SPP/TRC8 is thought to be related to other diseases as well thereby being potentially useful for the drug development for a variety of diseases.

###

This research was featured in the electronic version of Nature Communications on Wednesday, May 4, 2016 (British Time).

http://www.eurekalert.org/pub_releases/2016-07/ou-don072716.php

FDA Hepatitis Update/ VIEKIRA XR - DOSAGE AND ADMINISTRATION

FDA Hepatitis Update

On July 22, 2016 FDA approved VIEKIRA XR extended release tablets. VIEKIRA XR is a fixed dose combination tablet of previously approved antiviral drugs containing dasabuvir, a hepatitis C virus non-nucleoside NS5B palm polymerase inhibitor, ombitasvir, a hepatitis C virus NS5A inhibitor, paritaprevir, a hepatitis C virus NS3/4A protease inhibitor, and ritonavir, a CYP3A inhibitor, indicated for the treatment of adult patients with chronic hepatitis C virus (HCV):

• genotype 1b infection without cirrhosis or with compensated cirrhosis
• genotype 1a infection without cirrhosis or with compensated cirrhosis for use in combination with ribavirin.

VIEKIRA XR differs from VIEKIRA Pak in that all of the HCV antiviral drugs are now combined in one fixed dose combination tablet for once daily dosing. The daily mg dose of dasabuvir is higher, and dasabuvir is administered once daily as part of the fixed dose combination.

The recommended dosage of VIEKIRA XR is three tablets taken orally once daily. VIEKIRA XR must be taken with a meal.

The approval of VIEKIRA XR is based on comparability of bioavailability for each of the components in VIEKIRA XR compared to that of the previously approved formulations in VIEKIRA Pak. A clinical trial to evaluate the efficacy and safety of Viekira XR FDC was not required because the efficacy and safety of the components of VIEKIRA XR were established previously in six clinical trials enrolling 2,308 Chronic Hepatitis C patients with and without cirrhosis.

DOSAGE AND ADMINISTRATION
Testing Prior to Initiation of VIEKIRA XR
Prior to initiation of VIEKIRA XR, assess for laboratory and clinical evidence of hepatic decompensation.

Recommended Dosage in Adults
VIEKIRA XR is a 4-drug fixed-dose combination, extended-release tablet containing 200 mg of dasabuvir, 8.33 mg of ombitasvir, 50 mg of paritaprevir, and 33.33 mg of ritonavir. The recommended dosage of VIEKIRA XR is three tablets taken orally once daily.

• VIEKIRA XR must be taken with a meal because administration under fasting conditions may result in reduced virologic response and possible development of resistance.
• Swallow tablets whole. Splitting, crushing, or chewing tablets may compromise the extended-release performance, efficacy, and/or safety of VIEKIRA XR.
• For optimal release of dasabuvir, alcohol should not be consumed within 4 hours of taking VIEKIRA XR.   

VIEKIRA XR is used in combination with ribavirin (RBV) in certain patient populations (see Table 1). When administered with VIEKIRA XR, the recommended dosage of RBV is based on weight: 1000 mg/day for subjects

For patients with HCV/HIV-1 co-infection, follow the dosage recommendations in Table 1.
Table 1 shows the recommended VIEKIRA XR treatment regimen and duration based on patient population.

Table 1. Treatment Regimen and Duration by Patient Population (Treatment-Naïve or Interferon-Experienced)

Patient Population	Treatment*	Duration
Genotype 1a, without cirrhosis	VIEKIRA XR + ribavirin	12 weeks
Genotype 1a, with compensated cirrhosis (Child-Pugh A)	VIEKIRA XR + ribavirin	24 weeks**
Genotype 1b, with or without compensated cirrhosis (Child-Pugh A)	VIEKIRA XR	12 weeks

*Note: Follow the genotype 1a dosing recommendations in patients with an unknown genotype 1 subtype or with mixed genotype 1 infection.
**VIEKIRA XR administered with ribavirin for 12 weeks may be considered for some patients based on prior treatment history

Use in Liver Transplant Recipients
In liver transplant recipients with normal hepatic function and mild fibrosis (Metavir fibrosis score 2 or lower), the recommended duration of VIEKIRA XR with ribavirin is 24 weeks, irrespective of HCV genotype 1 subtype. When VIEKIRA XR is administered with calcineurin inhibitors in liver transplant recipients, dosage adjustment of calcineurin inhibitors is needed.

Hepatic Impairment
VIEKIRA XR is contraindicated in patients with moderate to severe hepatic impairment (Child Pugh B and C)
The complete label for VIEKIRA XR is available at Drugs@FDA.

VIEKIRA XR full Prescribing Information, including the Medication Guide.
VIEKIRA PAK full Prescribing Information, including the Medication Guide.

AbbVie Press Release
AbbVie Receives U.S. FDA Approval of Once-Daily VIEKIRA XR™ (dasabuvir, ombitasvir, paritaprevir and ritonavir) for the Treatment of Genotype 1 Chronic Hepatitis C

Know your hepatitis status – increasing access to testing for a hidden infection.

25 July 2016 – A staggering 95% of people infected with hepatitis B or C do not know they are infected, often living without symptoms for many years. Ahead of World Hepatitis Day, 28 July 2016, WHO and its partner, Social Entrepreneurship for Sexual Health (SeSH), recently launched a global contest to find innovative ways to reach different populations and encourage testing for hepatitis

Know your hepatitis status – increasing access to testing for a hidden infection.
July 2016 

Do you know if you could be infected with hepatitis B or C? What that could mean for your health?

A staggering 95% of people infected with hepatitis B or C around the world do not know they are infected. One reason for this is that people can live without symptoms for many years. When they find out they have hepatitis, it is often too late for treatment to be fully effective. As a result, liver damage becomes cirrhosis or liver cancer.

To help countries build up national hepatitis testing and treatment programmes and to encourage more people globally to get tested, WHO will shortly release new testing guidelines for hepatitis B and C.

To show how the testing guidelines could translate into real action on the ground, WHO and its partner, Social Entrepreneurship for Sexual Health (SeSH) recently launched a contest to find real-world examples of innovative ways to reach different populations across various countries and settings and test for hepatitis.

The #HepTestContest Innovation Contest received 64 contributions from 27 countries. The project selected around 20 of the best approaches to testing for hepatitis, and then whittled down the list to 5 finalists.

A multi-faceted approach

As well as national testing campaigns, approaches include testing in prisons, testing in the workplace and hospital emergency rooms, integrated HIV-hepatitis testing, as well as the use of internet, social media, and electronic medical records to flag higher risk patients for testing in primary care.

“We needed examples of innovations and best practices to help guide and inspire others,” said Philippa Easterbrook from the WHO Global Hepatitis Programme, who co-led the project. “From prisons in Australia, use of an internet-based risk self-assessment tool in the Netherlands, community testing camps for drug users in India, to testing in primary care in Mongolia we learned some great lessons about how to build awareness of this hidden disease, improve testing rates and link those infected to treatment and care.“

In Manipur, a small state in North East India, an estimated 92% to 98% of drug users are estimated to have hepatitis C. Although HIV testing is free here, testing for hepatitis is not. Awareness about the virus is low and treatment expensive.

A community network organization, the Community Network for Empowerment (CoNE) led the campaign: “We organized awareness-raising sessions, and encouraged free voluntary testing for over a month. Of the 1011 people tested, just under half were positive for hepatitis C. We provided post-test counselling and were also able to offer treatment,” described Rajkumar Nalinikanta, the organization’s president.

Community involvement and strategic partnerships

A critical feature of this approach was the strong community involvement and support as well as strategic partnerships to leverage reductions in the price of treatments. “Bringing together pharmaceutical companies, government, research organizations and communities helped negotiate price reductions make hepatitis treatments more affordable,” concluded Dr Easterbrook.”

Thousands of miles away in the Netherlands, another campaign used an internet-based risk assessment to target populations of people infected with hepatitis C who were difficult to identify and hard to reach.

“We used social media and the web to draw in people who might be at risk to undertake a self-assessment in a choice of 7 languages. The anonymity of the internet helped enormously,” said Janke Schinkel of the Public Health Service of Amsterdam. “This was balanced with highly visible and creative public communication campaigns – that reached a cross-section of Dutch society.”

“The contest demonstrated a range of possibilities. It showed that if we can develop acceptable testing approaches to suit different contexts and cultures, then we can increase effective hepatitis testing in more countries and communities,” concluded Dr Easterbrook.

These 2 approaches were among the 5 finalists selected by a panel of experts including representatives from WHO, World Hepatitis Alliance, and Médecins sans Frontières, who reviewed the testing models for innovation, effectiveness, and plans for sustainability.

http://www.who.int/en/

World Hepatitis Day 2016

News release for World Hepatitis Day 2016

Why baby boomers need a hepatitis C screening

Why baby boomers need a hepatitis C screening
26-Jul-2016

Electronic medical record alerts contribute to dramatic rise in HepC screening

University of Michigan Health System

Baby boomers, adults born between 1945 and 1965, are five times more likely to have been exposed to the hepatitis C virus (HCV).

As a result, the Centers for Disease Control and Prevention and the U.S. Preventive Service Task Force recommend that all patients in that age group get tested.

But the simple blood test, designed to detect and prevent illness before the virus wreaks havoc, is infrequently performed on baby boomers whose routine medical appointments are often crammed with other preventive measures and tests -- as well as time spent addressing active problems that require a doctor's immediate attention.

Investigators at the University of Michigan Health System recently found an easy way to help primary care physicians ensure that an HCV screening is part of the routine: Electronic medical record alerts.

The automated alert, programmed to appear if a patient was within the at-risk age group, reminds doctors not only to issue the test but also provide educational materials about the virus.

Implemented in fall 2015 in primary care clinics throughout the U-M health system, the strategy contributed to a significant rise in screenings -- an eightfold boost -- in the first six months alone.

"A large part of the success was figuring out how to take the logistical work away, which involves more than looking at a patient's date of birth," says Monica Konerman, M.D., M.Sc., a hepatologist at the University of Michigan who treats patients facing the prospect of hepatitis damaging their liver.

A population in need

It isn't entire clear why hepatitis C rates are higher in baby boomers -- although many, according to the CDC, are believed to have become infected during the 1970s and 80s when rates were highest (and before screenings of donated blood and organs became available in 1992).

Hepatitis C, likewise, can be asymptomatic for decades. Many patients could have been exposed to risk factors years ago but never sought testing or treatment.

A universal one-time HCV screening based on age, then, can bypass the discomfort of having to talk about potentially embarrassing topics such as prior drug use or sharing needles.

It also helps democratize preventive care. Prior to launching the alert, HCV screening was higher in men, Asian and African Americans, and in patients with Medicaid insurance. Screening rates also varied greatly by clinic site (ranging from 20 to 32 percent).

After the alert was adopted, however, screenings increased equally among genders, races, insurance plans and UMHS clinic sites.

Why screening matters

The screening test for hepatitis C is the virus antibody. If the hepatitis C antibody is detected, a confirmation test for the virus' RNA (genetic material) is recommended to confirm chronic infection.

Of the 16,773 baby boomers targeted for screening via electronic alert at UMHS, fewer than 1 percent tested positive for the hepatitis C antibody.

Despite that low rate, the alert system nonetheless helped identify people who would benefit from curative hepatitis C treatment, says Konerman, who presented the findings in May at the Digestive Disease Week conference in San Diego.

After all, a new era in hepatitis treatment began in 2013 with the approval of interferon-free oral combination therapy that was demonstrated in clinical trials studies led by the U-M to cure hepatitis C in 95 percent of patients. If treated and the body responds, patients can get rid of the virus before liver damage and liver failure occur.

Which is why the new alert technology is crucial for a population that could benefit most from HCV screening.

"The availability of direct-acting antiviral agents has been a game-changer," says Konerman. "Previously, many providers thought screening had low utility: (that) the treatment was terrible and didn't work well. Today, short courses of all oral treatments are highly effective and can prevent progressive liver disease."

http://www.med.umich.edu

Children Exposed To Hepatitis C May Be Missing Out On Treatment

Public Health

Children Exposed To Hepatitis C May Be Missing Out On Treatment
July 26, 20165:00 AM ET
Elana Gordon

Several times a month, Jessica Wen, a pediatrician specializing in liver diseases, has a teenager show up at her clinic at the Children's Hospital of Philadelphia with an unexpected diagnosis: hepatitis C.

Hepatitis C virus, or HCV, is the most common bloodborne infection in the U.S. and a leading cause of liver failure and cancer. Injection drug use is a common risk factor, as is receiving a blood transfusion before 1992. But some of the teens Wen sees picked up the illness another way: at birth, from their mothers.

"I have diagnosed moms after diagnosing the kids," Wen says, referring to mothers who have hepatitis C, didn't know it and then passed it to their babies during childbirth. Wen estimates that about 1 or 2 of every 1,000 young children have chronic hepatitis C.

A study by the Philadelphia Department of Health points to what Wen and others in the medical profession see as a worrisome trend: Children with hepatitis C may be unaware of their diagnosis and the potential need for treatments down the road in order to prevent long-term liver damage.

Using city surveillance data, the study found that as many as 8 in 10 children at high risk for hepatitis C exposure in Philadelphia were never screened for the condition. More specifically, of the approximately 500 moms-to-be who were registered as having hepatitis C between 2011 and 2013, only 84 of their newborns, or about 16 percent, were tested for the virus by 20 months of age.

"Sixteen percent is really low," says Danica Kuncio, lead author of the study. "When you think about children, you hope that the number would be 100 percent, that it should be in the interest of every provider to be doing the best they can to get information to the next provider."

Kuncio, an epidemiologist with the city, worries that people who don't know they contracted hepatitis C as babies won't get the health care they need or realize they could spread the virus to others through blood-to-blood contact. It's a concern intensified by a rise in both injection drug use and hepatitis C among women of childbearing age, she said.

"It's a call to arms to figure out how we can do this better," said Dr. Michael Narkewicz, who specializes in pediatric liver diseases and hepatitis C at the University of Colorado School of Medicine.

Not so long ago, the lack of drugs to cure hepatitis C made screening less of a priority. But in 2013, the Food and Drug Administration approved the first of several drugs that effectively eliminate the virus. Now, with access to these expensive medicines, the condition has gone from chronic and debilitating to curable.

Narkewicz and others say the next frontier is to prove these treatments are safe and effective in children. Clinical trials are underway, and he thinks the drugs could become available for children in the next year or two.

But unlike HIV, which has safe and effective treatments that can dramatically reduce transmission of the virus from mother to child, "for hepatitis C, there are no treatments to prevent transmission in a mom or in a newborn," said Narkewicz.

Hepatitis C in children may be lacking attention for another reason: perinatal transmission rates are a lot lower for Hepatitis C compared to hepatitis B and HIV. For every 100 babies born to women with HCV, five to seven will contract the virus. Of those who do get it, 30 to 40 percent will clear it on their own before the age of two, said Narkewicz. That's why the current protocols for children exposed to HCV call for monitoring and then screening them at 18 months with an antibody test.

But up to 15 percent of those born with HCV will develop a more aggressive form of the disease during adolescence, said Narkewicz, which can result in advanced fibrosis or liver scarring that can progress over time. "It's a small percentage, but it's still a real number," he said.

The medical community really hasn't done a good job of projecting the costs and benefits of early identification and treatment in children, according to Dr. Rhavi Javeri, a pediatrician at UNC Children's Hospital in Chapel Hill, N.C.

"A lot of these other issues related to mom-to-infant transmission, it really all fallen by the wayside," Javeri says. "[The conversation] still falls on, we don't have resources to treat patients that are the priority right now."

Having new drugs to treat hepatitis C in children will be a game-changer, according to Dr. Regino Gonzalez-Peralta, a pediatrician at the University of Florida Health System in Gainesville.

"The old dogma was, why screen mothers if there's nothing to be done?" says Gonzalez-Peralta, who has also been studying gaps in identifying children infected with HCV.

He says that while drugs to prevent transmission are not yet available, there are promising developments. "Now we've got drugs that potentially might be useful in preventing maternal-fetal transmission. This is going to become a hotter area," he says.

Another issue under debate is universal screening for the virus. Dr. Damien Croft, an obstetrician at Hahnemann University Hospital in Philadelphia, doesn't advocate it for everyone in the country. But he thinks it might be a good idea for his pool of patients. "There [are] enough women who are high risk for hepatitis C in Philadelphia that maybe we should consider doing that."

Croft also thinks it's important to improve communication between obstetricians and pediatricians so the pediatrician will know which children are at higher risk for having hepatitis C and can recommend screening.

In the meantime, Philadelphia's health department has begun working with health care providers and at-risk mothers in the city to improve the testing of infants born to women with hepatitis C, and when necessary, linking mother or child to specialists.

This story is part of a reporting partnership with NPR, WHYY's health show The Pulse and Kaiser Health News.

http://www.npr.org

Also See;
Earlier Identification of HCV in Young Women, Babies Needed​

(MMWR) Increased Hepatitis C Detection in Women of Childbearing Age and Potential Risk for Vertical Transmission

Shared Drug Snorting Straws May Transmit Hepatitis C Virus
FRIDAY, July 22, 2016 (HealthDay News) -- Sharing snorting straws for noninjection drug use may be a source for hepatitis C virus (HCV) transmission, according to research published in the August issue of Obstetrics & Gynecology.
Here is the report; Sharing of snorting straws and hepatitis C virus infection in pregnant women

FDA approves a New Drug Application (NDA) for VIEKIRA XR™ (dasabuvir, ombitasvir, paritaprevir and ritonavir)

VIEKIRA XR differs from VIEKIRA Pak in that all of the HCV antiviral drugs are now combined in one fixed dose combination tablet for once daily dosing. The daily mg dose of dasabuvir is higher, and dasabuvir is administered once daily as part of the fixed dose combination.

VIEKIRA XR is a once-daily, extended-release co-formulation of the active ingredients in VIEKIRA PAK® (ombitasvir, paritaprevir, and ritonavir tablets; dasabuvir tablets) and is for the treatment of patients with chronic genotype 1 (GT1) hepatitis C virus (HCV) infection, including those with compensated cirrhosis (Child-Pugh A). VIEKIRA XR is not for people with decompensated cirrhosis.

VIEKIRA XR full Prescribing Information, including the Medication Guide.
VIEKIRA PAK full Prescribing Information, including the Medication Guide.

FDA Hepatitis Update

On July 22, 2016 FDA approved VIEKIRA XR extended release tablets. VIEKIRA XR is a fixed dose combination tablet of previously approved antiviral drugs containing dasabuvir, a hepatitis C virus non-nucleoside NS5B palm polymerase inhibitor, ombitasvir, a hepatitis C virus NS5A inhibitor, paritaprevir, a hepatitis C virus NS3/4A protease inhibitor, and ritonavir, a CYP3A inhibitor, indicated for the treatment of adult patients with chronic hepatitis C virus (HCV):

• genotype 1b infection without cirrhosis or with compensated cirrhosis
• genotype 1a infection without cirrhosis or with compensated cirrhosis for use in combination with ribavirin.

VIEKIRA XR differs from VIEKIRA Pak in that all of the HCV antiviral drugs are now combined in one fixed dose combination tablet for once daily dosing. The daily mg dose of dasabuvir is higher, and dasabuvir is administered once daily as part of the fixed dose combination.

The recommended dosage of VIEKIRA XR is three tablets taken orally once daily. VIEKIRA XR must be taken with a meal.

The approval of VIEKIRA XR is based on comparability of bioavailability for each of the components in VIEKIRA XR compared to that of the previously approved formulations in VIEKIRA Pak. A clinical trial to evaluate the efficacy and safety of Viekira XR FDC was not required because the efficacy and safety of the components of VIEKIRA XR were established previously in six clinical trials enrolling 2,308 Chronic Hepatitis C patients with and without cirrhosis.

DOSAGE AND ADMINISTRATION
Testing Prior to Initiation of VIEKIRA XR
Prior to initiation of VIEKIRA XR, assess for laboratory and clinical evidence of hepatic decompensation.

Recommended Dosage in Adults
VIEKIRA XR is a 4-drug fixed-dose combination, extended-release tablet containing 200 mg of dasabuvir, 8.33 mg of ombitasvir, 50 mg of paritaprevir, and 33.33 mg of ritonavir. The recommended dosage of VIEKIRA XR is three tablets taken orally once daily.

• VIEKIRA XR must be taken with a meal because administration under fasting conditions may result in reduced virologic response and possible development of resistance.
• Swallow tablets whole. Splitting, crushing, or chewing tablets may compromise the extended-release performance, efficacy, and/or safety of VIEKIRA XR.
• For optimal release of dasabuvir, alcohol should not be consumed within 4 hours of taking VIEKIRA XR.   

VIEKIRA XR is used in combination with ribavirin (RBV) in certain patient populations (see Table 1). When administered with VIEKIRA XR, the recommended dosage of RBV is based on weight: 1000 mg/day for subjects

For patients with HCV/HIV-1 co-infection, follow the dosage recommendations in Table 1.
Table 1 shows the recommended VIEKIRA XR treatment regimen and duration based on patient population.

Table 1. Treatment Regimen and Duration by Patient Population (Treatment-Naïve or Interferon-Experienced)

Patient Population	Treatment*	Duration
Genotype 1a, without cirrhosis	VIEKIRA XR + ribavirin	12 weeks
Genotype 1a, with compensated cirrhosis (Child-Pugh A)	VIEKIRA XR + ribavirin	24 weeks**
Genotype 1b, with or without compensated cirrhosis (Child-Pugh A)	VIEKIRA XR	12 weeks

*Note: Follow the genotype 1a dosing recommendations in patients with an unknown genotype 1 subtype or with mixed genotype 1 infection.
**VIEKIRA XR administered with ribavirin for 12 weeks may be considered for some patients based on prior treatment history

Use in Liver Transplant Recipients
In liver transplant recipients with normal hepatic function and mild fibrosis (Metavir fibrosis score 2 or lower), the recommended duration of VIEKIRA XR with ribavirin is 24 weeks, irrespective of HCV genotype 1 subtype. When VIEKIRA XR is administered with calcineurin inhibitors in liver transplant recipients, dosage adjustment of calcineurin inhibitors is needed.

Hepatic Impairment
VIEKIRA XR is contraindicated in patients with moderate to severe hepatic impairment (Child Pugh B and C)
The complete label for VIEKIRA XR is available at Drugs@FDA.

AbbVie Press Release
AbbVie Receives U.S. FDA Approval of Once-Daily VIEKIRA XR™ (dasabuvir, ombitasvir, paritaprevir and ritonavir) for the Treatment of Genotype 1 Chronic Hepatitis C

Jul 25, 2016

- New extended-release formulation is the first all-oral, co-formulated treatment containing the three direct-acting antiviral components of VIEKIRA PAK® for adult patients with genotype 1 (GT1) chronic hepatitis C virus (HCV) infection

- The approval marks another milestone in AbbVie's ongoing commitment to therapeutic innovation for people living with GT1 HCV

NORTH CHICAGO, Ill., July 25, 2016 /PRNewswire/ -- AbbVie (NYSE: ABBV), a global biopharmaceutical company, today announced that the U.S. Food and Drug Administration (FDA) has approved a New Drug Application (NDA) for VIEKIRA XR™ (dasabuvir, ombitasvir, paritaprevir and ritonavir) extended-release tablets. VIEKIRA XR is a once-daily, extended-release co-formulation of the active ingredients in VIEKIRA PAK® (ombitasvir, paritaprevir, and ritonavir tablets; dasabuvir tablets) and is for the treatment of patients with chronic genotype 1 (GT1) hepatitis C virus (HCV) infection, including those with compensated cirrhosis (Child-Pugh A). VIEKIRA XR is not for people with decompensated cirrhosis.

VIEKIRA XR is the first co-formulated three direct-acting antiviral (DAA) treatment for adult patients with GT1 HCV. VIEKIRA XR is given once-daily as three oral tablets and must be taken with a meal. It is used without ribavirin (RBV) in GT1b patients and in combination with twice daily RBV in GT1a patients. The approval is supported by Phase 3 clinical trials for VIEKIRA PAK which include data that demonstrated 100 percent sustained virologic response 12 weeks following treatment (SVR12) in GT1b patients with 12 weeks of therapy without ribavirin and 95 percent SVR12 in GT1a patients when used with ribavirin for 12 or 24 weeks of therapy.

"AbbVie's work continues to contribute to the transformation of hepatitis C care through our focus on evolving our current therapies as part of our ongoing commitment to patients," said Rob Scott, M.D., vice president, development and chief medical officer, AbbVie. "The approval of VIEKIRA XR provides a new treatment option for genotype 1 hepatitis C patients in the U.S. with clinical trial data using the components of VIEKIRA XR demonstrating 100 percent cure rates in genotype 1b patients."

There are six major HCV genotypes (GT1-6) and GT1 is the most prevalent form of HCV in the U.S., accounting for approximately 74 percent of all cases.1 Hepatitis C continues to be an important public health issue, with the Centers for Disease Control and Prevention (CDC) estimating that in the U.S. approximately 2.7 million people are chronically infected with HCV.2

The approval of VIEKIRA XR is supported by data from seven Phase 3 clinical trials in more than 2,300 patients who received VIEKIRA PAK with or without RBV for 12 or 24 weeks and two bioavailability studies comparing the formulations.

About Clinical Studies

The components of VIEKIRA XR (administered twice daily with a meal) have been studied in seven Phase 3 clinical trials where 1076 subjects (including 181 with compensated cirrhosis) received the recommended regimen of VIEKIRA +/? RBV for 12 weeks, or for 24 weeks in GT1a patients with compensated cirrhosis. Ninety-five to 100 percent achieved SVR12, which means the hepatitis C virus is not detectable in the blood three months after treatment ends. Cure rates varied by the subtype of hepatitis C and whether or not the person had cirrhosis. Individual results may vary.

USE

VIEKIRA XR™ (dasabuvir, ombitasvir, paritaprevir, and ritonavir) extended-release tablets/VIEKIRA PAK® (ombitasvir, paritaprevir, and ritonavir tablets; dasabuvir tablets) (VIEKIRA) are prescription medicines used with or without ribavirin to treat adults with genotype 1 chronic (lasting a long time) hepatitis C (hep C) virus infection.

VIEKIRA can be used in people who have compensated cirrhosis.

VIEKIRA is not for people with advanced cirrhosis (decompensated). If people have cirrhosis, they should talk to a doctor before taking VIEKIRA.

IMPORTANT SAFETY INFORMATION

When taking VIEKIRA in combination with ribavirin, people should read the Medication Guide that comes with ribavirin, especially the important pregnancy information.

What is the most important information to know about VIEKIRA?
VIEKIRA may cause severe liver problems, especially in people with certain types of cirrhosis. These severe liver problems can lead to the need for a liver transplant, or can lead to death.
VIEKIRA can cause increases in liver function blood test results, especially if people use ethinyl estradiol-containing medicines (such as some birth control products).
Ethinyl estradiol-containing medicines (combination birth control pills or patches, such as Lo Loestrin® FE, Norinyl®, Ortho Tri-Cyclen Lo®, Ortho Evra®; hormonal vaginal rings such as NuvaRing®; and the hormone replacement therapy medicine, Fem HRT®) must be stopped before starting treatment with VIEKIRA. If these medicines are used as a method of birth control, another method must be used during treatment with VIEKIRA, and for about 2 weeks after treatment with VIEKIRA ends. A doctor can provide instruction on when to begin taking ethinyl estradiol-containing medicines.
A doctor should do blood tests to check liver function during the first 4 weeks of treatment and then as needed.
A doctor may tell people to stop taking VIEKIRA if signs or symptoms of liver problems develop. A doctor must be notified right away if any of the following symptoms develop or if they worsen during treatment with VIEKIRA: tiredness, weakness, loss of appetite, nausea, vomiting, yellowing of the skin or eyes, color changes in stools, confusion, or swelling of the stomach area.

VIEKIRA must not be taken if people:
have certain liver problems
take any of the following medicines: alfuzosin hydrochloride (Uroxatral®) • carbamazepine (Carbatrol®, Epitol®, Equetro®, Tegretol®, TEGRETOL®-XR, TERIL®) • cisapride (Propulsid®) • colchicine (Colcrys®), in patients who have certain kidney or liver problems • dronedarone (Multaq®) • efavirenz (Atripla®, Sustiva®) • ergot-containing medicines, including ergotamine tartrate (Cafergot®, Ergomar®, Ergostat®, Medihaler®, Migergot®, Wigraine®, Wigrettes®), dihydroergotamine mesylate (D.H.E. 45®, Migranal®), methylergonovine (Ergotrate®, Methergine®) • ethinyl estradiol-containing medicines • gemfibrozil (Lopid®) • lovastatin (Advicor®, Altoprev®, Mevacor®) • lurasidone (Latuda®) • midazolam (when taken by mouth) • phenytoin (Dilantin®, Phenytek®) • phenobarbital (Luminal®) • pimozide (Orap®) • ranolazine (Ranexa®) • rifampin (Rifadin®, Rifamate®, Rifater®, Rimactane®) • sildenafil citrate (Revatio®), when taken for pulmonary artery hypertension (PAH) • simvastatin (Simcor®, Vytorin®, Zocor®) • St. John's wort (Hypericum perforatum) or a product that contains St. John's wort • triazolam (Halcion®)
have had a severe skin rash after taking ritonavir (Norvir®)

What should people tell a doctor before taking VIEKIRA?
If they have: liver problems other than hep C infection, HIV infection, or any other medical conditions.
If they have had a liver transplant.
If they take the medicines tacrolimus (Prograf®) or cyclosporine (Gengraf®, Neoral®, Sandimmune®), a doctor should check blood levels and, if needed, may change the dose of these medicines or how often they are taken, both during and after treatment with VIEKIRA.
If they are pregnant or plan to become pregnant or if they are breastfeeding or plan to breastfeed. It is not known if VIEKIRA will harm a person's unborn baby or pass into breast milk. A doctor should be consulted about the best way to feed a baby if taking VIEKIRA.
About all the medicines they take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Some medicines interact with VIEKIRA.
A new medicine must not be started without telling a doctor. A doctor will provide instruction on whether it is safe to take VIEKIRA with other medicines.
When VIEKIRA is finished, a doctor should be consulted on what to do if one of the usual medicines taken was stopped or if the dose changed during VIEKIRA treatment.

What are the common side effects of VIEKIRA?
For VIEKIRA used with ribavirin, side effects include tiredness, nausea, itching, skin reactions such as redness or rash, sleep problems, and feeling weak.
For VIEKIRA used without ribavirin, side effects include nausea, itching, and sleep problems.

These are not all of the possible side effects of VIEKIRA. A doctor should be notified if there is any side effect that is bothersome or that does not go away.

This is the most important information to know about VIEKIRA. For more information, talk to a doctor.

People are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

Please see VIEKIRA XR full Prescribing Information, including the Medication Guide.

Please see VIEKIRA PAK full Prescribing Information, including the Medication Guide.

If people cannot afford their medication, they should contact www.pparx.org for assistance.

About VIEKIRA XR

The components of VIEKIRA XR* have been studied in a broad range of genotype 1 (GT1) patients with chronic hepatitis C virus (HCV) infection, ranging from treatment-naïve to difficult to treat patients, such as those with compensated (mild, Child-Pugh A) cirrhosis of the liver, HCV/HIV-1 co-infection, liver transplant recipients with normal hepatic function and mild fibrosis, and those who have failed previous treatment with pegylated interferon (pegIFN) and ribavirin (RBV).

The extended-release co-formulation of these components, VIEKIRA XR, consists of 200 mg of dasabuvir, 8.33 mg of ombitasvir, 50 mg of paritaprevir, and 33.33 mg of ritonavir per tablet, and is dosed three tablets once daily. VIEKIRA XR must be taken with a meal, and tablets should be swallowed whole. People should not drink alcohol within four hours of taking VIEKIRA XR. VIEKIRA XR is contraindicated in patients with moderate to severe hepatic impairment (Child-Pugh B and C) due to risk of potential toxicity. VIEKIRA XR is taken for 12 weeks, except in GT1a patients with cirrhosis and all liver transplant recipients with normal hepatic function and mild fibrosis, who should take it for 24 weeks. Ribavirin should be co-administered in GT1a patients and in all patients who have received a liver transplant.

Paritaprevir was discovered during the ongoing collaboration between AbbVie and Enanta Pharmaceuticals (NASDAQ: ENTA) for HCV protease inhibitors and regimens that include protease inhibitors. Paritaprevir is used in combination with AbbVie's ombitasvir with or without dasabuvir for the treatment of hepatitis C.

*Given as a fixed-dose combination of ombitasvir 25mg (an NS5A inhibitor), paritaprevir 150mg (an NS3/4A protease inhibitor), and ritonavir 100mg (an HIV-1 protease inhibitor), dosed once daily with a meal, and dasabuvir 250mg (a non-nucleoside NS5B palm polymerase inhibitor), dosed twice daily with a meal.

About AbbVie's Patient Assistance Program

AbbVie supports patient assistance programs to help qualified people access their needed AbbVie medication at no cost. In 2015, more than 81,000 U.S. patients received AbbVie's medicines at no cost3. For those who qualify, AbbVie plans to offer a patient assistance program for people taking VIEKIRA XR. Since VIEKIRA PAK's approval in 2014, AbbVie has supported access to medication for those living with chronic HCV and facing financial difficulties.

About AbbVie's HCV Clinical Development Program

AbbVie's HCV clinical development program is intended to advance scientific knowledge and the clinical care of people with chronic HCV infection. AbbVie is investigating a pan-genotypic (genotypes 1-6) regimen and is in Phase 3 of clinical development. For more information on AbbVie Phase 3 HCV studies, visit www.clinicaltrials.gov (NCT02243293).

About HCV

Hepatitis C is inflammation of the liver caused by an infection with the hepatitis C virus. It is transmitted when an infected person's blood enters the bloodstream of an uninfected person. The Centers for Disease Control (CDC) estimates that approximately 2.7 million people have chronic HCV infection in the U.S. There are six major HCV genotypes (GT1-6), with genotype 1 (GT1) as the most prevalent form in the U.S. It is estimated that of people infected with chronic HCV, about 5 to 20 percent will go on to develop cirrhosis over a period of 20–30 years, and with HCV-related liver transplants on the rise, HCV is a critical public health issue. Presently, there is no vaccine for HCV infection.

About AbbVie

AbbVie is a global, research-based biopharmaceutical company formed in 2013 following separation from Abbott Laboratories. The company's mission is to use its expertise, dedicated people and unique approach to innovation to develop and market advanced therapies that address some of the world's most complex and serious diseases. Together with its wholly-owned subsidiary, Pharmacyclics, AbbVie employs more than 28,000 people worldwide and markets medicines in more than 170 countries. For further information on the company and its people, portfolio and commitments, please visit www.abbvie.com. Follow @abbvie on Twitter or view careers on our Facebook or LinkedIn page.

Forward-Looking Statements

Some statements in this news release may be forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995. The words "believe," "expect," "anticipate," "project" and similar expressions, among others, generally identify forward-looking statements. AbbVie cautions that these forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those indicated in the forward-looking statements. Such risks and uncertainties include, but are not limited to, challenges to intellectual property, competition from other products, difficulties inherent in the research and development process, adverse litigation or government action, and changes to laws and regulations applicable to our industry.

Additional information about the economic, competitive, governmental, technological and other factors that may affect AbbVie's operations is set forth in Item 1A, "Risk Factors," of AbbVie's 2015 Annual Report on Form 10-K, which has been filed with the Securities and Exchange Commission. AbbVie undertakes no obligation to release publicly any revisions to forward-looking statements as a result of subsequent events or developments, except as required by law.

1 Wedemeyer H. Hepatitis C. Chapter 80: In: Feldman M, Friedman LS, Brandt LJ, eds. Sleisenger and Fordtran's Gastrointestinal and Liver Disease. Vol 2. 10th ed. Philadelphia, PA: Saunders Elsevier; 2016.
2 Centers for Disease Control and Prevention (CDC). Hepatitis C FAQs for health professionals. http://www.cdc.gov/hepatitis/hcv/hcvfaq.htm#section1. Accessed June 9, 2016.
3 AbbVie 2016 Impact by the Numbers. http://www.abbvie.com/responsibility/home.html