October 27, 2013

BY BRUCE GOLDMAN

OCT. 21, 2013

In a feat of modern-day alchemy with huge potential for regenerative medicine, Stanford University School of Medicine scientists have developed a fast, efficient way to turn cells extracted from routine liposuction into liver cells.

The advance is described in a study published Oct. 21 in Cell Transplantation.

The scientists performed their experiments in mice, but the adipose stem cells they used came from human liposuction aspirates and became human, liver-like cells that flourished inside the mice’s bodies. This method is distinct from those producing liver cells from embryonic stem cells or induced pluripotent stem cells. Although iPS and embryonic stem cells are pluripotent — they can, in principle, differentiate into every cell type — they carry a palpable risk of forming tumors.

However, the cells produced using this new technique, which involves no intermediate pluripotent phase, show no signs of being tumorogenic.

The liver is the body’s chemistry set. It builds complex biomolecules we need, and it filters and breaks down waste products and toxic substances that might otherwise accumulate to dangerous levels. Unlike most other organs, a healthy liver can regenerate itself to a significant extent. But this capacity cannot overcome acute liver poisoning or damage from chronic alcoholism or viral hepatitis.

Acute liver failure from acetaminophen alone takes about 500 lives annually and accounts for close to 60,000 emergency-room visits and more than 25,000 hospitalizations annually. Other environmental toxins, including poisonous mushrooms, contribute still more cases.

All aspects of the new fat-to-liver technique are adaptable for human use, said Gary Peltz, MD, PhD, professor of anesthesia and the study’s senior author. Creating iPS cells requires introducing foreign and potentially carcinogenic genes. But adipose stem cells merely have to be harvested from fat tissue. The process takes nine days from start to finish — fast enough to regenerate liver tissue in acute liver poisoning victims, who would otherwise die within a few weeks, barring liver transplantation.

Some 6,300 liver transplants are performed annually in the United States, with another 16,000 patients on the waiting list. Every year, more than 1,400 people die before a suitable liver can be found for them. While it can save lives, liver transplantation is complicated, risky and, even when successful, fraught with aftereffects. Typically, the recipient is consigned to a lifetime of taking immunosuppressant drugs to prevent organ rejection.

“We believe our method will be transferable to the clinic,” Peltz said. “And because the new liver tissue is derived from a person’s own cells, we do not expect that immunosuppressants will be needed.”

Liver cells are not something an adipose stem cell normally wants to turn into, Peltz said.

The Stanford team knew it was possible, though. Another way of converting liposuction-derived adipose stem cells to liver-like cells (called i-Heps, for induced hepatocytes) had been developed in 2006 by Japanese researchers. But that method, which relies on chemical stimulation, requires 30 days or longer and is inefficient; it could not produce enough material for liver reconstitution. (Working with iPS cells takes even longer; they must first be generated from adult cells before they can be converted to i-Heps.)

Using a different technique — Peltz refers to it as spherical culture — he and his associates were able to achieve the conversion within nine days with an efficiency of 37 percent, as opposed to the vastly lower yield obtained with the prior method (12 percent) or using iPS cells. (Peltz said improvements since the study’s publication now enable yields exceeding 50 percent within seven to eight days.)

Dan Xu, PhD, a postdoctoral scholar and the study’s lead author, adapted the spherical culture methodology from early embryonic-stem-cell literature. Instead of growing on flat surfaces in a laboratory dish, the harvested adipose stem cells are cultured in a liquid suspension in which they form spheroids. “This seems to make them happier,” Peltz said.

When they had enough cells, the investigators tested them by injecting them into immune-deficient laboratory mice that accept human grafts. These mice were bioengineered in 2007, in a collaboration between Peltz’s lab and study co-author Toshihiko Nishimura, MD, PhD, and other scientists at the Tokyo-based Central Institute for Experimental Animals. Only the livers of these mice contained an extra gene that would convert the antiviral compound gancyclovir into a potent toxin. When these mice were treated with gancyclovir, their liver cells died off quickly.

At this point the investigators injected 5 million i-Heps into the mice’s livers. To do that — no mean feat, as these tiny organs weigh a scant 1.8 grams — they used an ultrasound-guided injection procedure that is routinely employed in gastroenterological clinics for biopsies.

Four weeks later, the investigators examined the mice’s blood and found the presence of a protein (human serum albumin) that is only produced by human liver cells and was shown to be an accurate proxy for the number of new human liver cells in these experimental mice’s livers. The mice’s blood had substantial human serum albumin levels, which nearly tripled in the following four weeks. These blood levels correspond with the repopulation of roughly 10-20 percent of the mice’s pre-destroyed livers by new human liver tissue. (Past studies have shown only miniscule human serum albumin production, at best, in mice given similar amounts of chemically induced i-Heps.)

Blood tests also revealed that the mice’s new liver tissue was discharging its waste-filtration responsibility. Examination of the livers themselves showed that the transplanted cells had integrated into the liver, expressed surface markers unique to mature human hepatocytes and produced multi-cell structures required for human bile duct formation. Other tests indicated that the spherically cultured i-Heps resembled natural human hepatocytes more closely than did i-Heps produced from iPS cells.

Importantly, two months after injection of i-Heps produced by spherical culture, there was no evidence of tumor formation. But mice in which IPS-cell-originated i-Heps were introduced developed multiple tumors, which could be felt through the body surface within three weeks.

At 1,500 grams, a healthy human liver is more than 800 times the size of a mouse’s and contains about 200 billion cells. “To be successful, we must regenerate about half of the damaged liver’s original cell count,” said Peltz. With spherical culture, he said, close to a billion injectable iHeps can be produced from 1 liter of liposuction aspirate, readily obtained from a single liposuction procedure. The cell replication that takes place after injection expands that number further, to over 100 billion i-Heps.

That could be enough to substitute for a human liver transplant, Peltz said. Stanford’s Office of Technology Licensing has filed a patent on the use of spherical culture for hepatocyte induction. Peltz’s group is optimizing the culture and injection techniques, talking to the U.S. Food and Drug Administration, and gearing up for safety tests on large animals. Barring setbacks, the new method could be ready for clinical trials within two to three years, he estimated.

Additional Stanford co-authors were Jeffrey Glenn, MD, PhD, associate professor of medicine; Sara Michie, MD, professor of pathology; Gordon Lee, MD, associate professor of plastic surgery; and research associates Ming Zheng, PhD, and Manhong Wu, PhD.

The study was funded by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases (grant 1R01DK0909921).

Information about Stanford Medicine’s Department of Anesthesia, which also supported the work, is available at http://med.stanford.edu/anesthesia.

Source

Hepatitis C Screening and Evaluation: Clinical Decision Tool

Gastroenterology
Volume 145, Issue 5 , Pages 1144-1145, November 2013

John I. Allen

Publication of the Clinical Decision Tool (CDT) for Hepatitis C Screening and Evaluation marks a milestone for the American Gastroenterological Association (AGA). This CDT is the first in a series of care pathways created for the “Clinical Service Lines” (CSL) component of AGA's “Roadmap to the Future of GI” initiative. The Roadmap to the Future of GI is designed to provide gastroenterologists with a single source for clinical tools needed to practice within the emerging value-based reimbursement environment. These tools have been created using a process steeped in the scientific rigor characteristic of AGA publications, combined with immediate access and the applicability needed for clinical practice.

The Roadmap to the Future of GI was originally presented to the AGA Governing Board during its strategy retreat in July 2011. It was first described in a July 2012 article in Clinical Gastroenterology and Hepatology1 and subsequent sections of the AGA website (www.gastro.org). The AGA initially committed to fully develop 3 CSL including (a) Hepatitis C Screening and Evaluation; (b) Colorectal Cancer Prevention; and (c) Inflammatory Bowel Disease. Beginning components of these 3 CSL can be referenced within the Practice Section of the AGA website.

The following components populate each CSL:

1.Clinical practice guidelines

2.Clinical Decision Tool

3.Performance measures

4.Methods to collect data on performance measures

5.Guides to reimbursement

6.Patient tools

7.Professional education

Hepatitis C virus (HCV) was endorsed as an important first CSL because of the substantial impact of chronic HCV infection on the adult population, the new recommendation for population-based screening and the enormous progress made in its treatment.2, 3, 4 Chronic HCV infection is a leading cause of liver disease, cirrhosis, hepatocellular cancer, liver transplantation, and death.5 Newly developed therapies, including direct acting antiviral therapies, have been developed and it is likely that therapies will become entirely oral and of shorter duration compared with traditional interferon-based treatments.5

Within the last year, the Centers for Disease Control and the United States Preventative Services Task Force both recommended one time screening for HCV for all people born between 1945 and 1965 in an effort to identify the 2.7–3.9 million Americans who are living with a chronic HCV infection.2, 3 Seventy-six percent of those infected with HCV are contained within this age group, and an estimated 45%–85% of those people with HCV are unaware they are infected, with 15%–40% expected to eventually develop cirrhosis or cancer.

It is clear that the burden of age cohort-based HCV screening, not to mention subsequent management of screen-positive patients, will overwhelm the capacity of United States hepatologists. General gastroenterologists must engage in HCV management to the highest level of their comfort. As a result of this sobering realization, the AGA, in partnership with the American Association for Study of Liver Disease (AASLD), set out to develop an easy-to-use care pathway with evidence-based recommendations for managing the initial phase of HCV evaluation.

An initial advisory group met in October 2012 in Chicago, IL. The final Task Force (listed at the end of this article) developed the CDT and evaluated each of its 15 decision points as part of a series of meetings and teleconferences from January to June of 2013. We gratefully acknowledge the participation of physician leaders and staff from the AGA, AASLD, and the Infectious Disease Society of America, plus practice leaders from both academic and community gastroenterology practices.

This CDT will aid gastroenterologists in the early management of HCV-positive patients and is intended to become a map for both clinical practice and construction of standard order sets, alerts, and dynamic point of care feedback within electronic medical records. The unique aspect of this CDT is that each decision point was evaluated and graded for its strength of evidence and strength of recommendation. Using the CDT, gastroenterologists can complete an evidence-based, cost-effective initial evaluation of patients whose screening for HCV is positive. It is important to emphasize that initial HCV screening positivity is not sufficient to begin therapy since further testing should confirm infection and must be coupled with expert evaluation of liver status including inflammation and histologic stage. Treatment of HCV infection was not included in this CDT since therapies are changing rapidly, however, care delivery infrastructure will need to adapt quickly in order to manage the number of expected HCV infected patients and the complexities of emerging therapies. Programs like Extension for Community Healthcare Outcomes (ECHO), represent a model of treatment that might help with capacity management.6

As the United States moves into a health care delivery world constrained by financial pressures and characterized by accountable care, risk contracting for population management, and reimbursements tied to outcomes, the tools created by the AGA will aid gastroenterologists to redesign their practice to meet these challenges. AGA leadership and staff hope that clinical decision tools like this and other tools within the Roadmap to the Future of GI will support the critical role that gastroenterologists play in providing care for the people that entrust us with their lives and health.

Appendix

The Hepatitis C Task Force includes: Mark D. Boldt, RN, CNP, Minnesota Gastroenterology; Joel V. Brill, MD, AGAF, Predictive Health; Gary L. Davis, MD, Baylor University Medical Center Dallas(retired); Stuart C. Gordon, MD, AGAF, Henry Ford Health System; Arthur Y. Kim, MD, FIDSA, Massachusetts General Hospital; Lawrence R. Kosinski, MD, MBA, AGAF, Illinois Gastroenterology Group; Arnold G. Levy, MD, Capital Digestive Care; Ronald G. Nahass, MD, MHCM, FIDSA, ID Care; John I. Allen, MD, MBA, AGAF (Chair), Yale School of Medicine.

References

Conflicts of interest The author discloses no conflicts.

PII: S0016-5085(13)01286-9

doi:10.1053/j.gastro.2013.09.008

© 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

Source


Gastroenterology
Volume 145, Issue 5 , Pages 1146-1149, November 2013

Hepatitis C Screening: Summary of Recommendations From the Clinical Decision Tool

The Hepatitis C Task Force, Mark D. Boldt, RN, CNP, Joel V. Brill, MD, AGAF, Gary L. Davis, MD, Stuart C. Gordon, MD, AGAF, Arthur Y. Kim, MD, FIDSA, Lawrence R. Kosinski, MD, MBA, AGAF, Arnold G. Levy, MD, Ronald G. Nahass, MD, MHCM, FIDSA, John I. Allen, MD, MBA, AGAF (Chair)

Decision Point 1: Adults Born Between 1945–1965 Who Have Never Been Evaluated for HCV 

Strong Recommendation Based on Strong Evidence

•Adults born between 1945 and 1965 should receive one-time testing for HCV without prior ascertainment of HCV risk (CDC Recommendation).1

•The US Preventive Services Task Force (USPSTF) recommends that clinicians consider offering screening for HCV infection in adults born between 1945 and 1965 (USPSTF GRADE B recommendation).2

Decision Point 2: Those at High Risk, Including Any Blood Transfusions Prior to 1992, or History of Intravenous Drug Use 

Strong Recommendation Based on Strong Evidence

•The USPSTF recommends screening for HCV infection in adults at high risk, including those with any history of intravenous drug use or blood transfusions prior to 1992 (USPSTF GRADE B Recommendation).2

Decision Point 3: Testing for Current Intravenous Drug Users 

Strong Recommendation based on Strong Evidence

•The USPSTF recommends screening for HCV infection in adults at high risk, including those with any history of intravenous drug use or blood transfusions prior to 1992 (USPSTF Grade B recommendation).2

Decision Point 4: Hepatitis C Antibody Testing 

Strong Recommendation Based on Strong Evidence

•A person whose anti-HCV test is reactive should be considered to either (1) have current HCV infection or (2) have had HCV infection in the past that has subsequently resolved (ie, cleared). To identify persons with active HCV infection, persons who initially test anti-HCV positive should be tested by an HCV nucleic acid test (NAT).2

Decision Point 5: Quantitative HCV RNA Testing 

Strong Recommendation Based on Strong Evidence

•HCV ribonucleic acid (RNA) testing should be performed in:

(a)Patients with a positive anti-HCV test (Class IB).

(b)Patients for whom antiviral treatment is being considered, using a sensitive quantitative assay (Class IA).

(c)Patients with unexplained liver disease whose anti-HCV test is negative and who are immunocompromised or suspected of having acute HCV infection (Class IB).3

•HCV RNA should be tested by a highly sensitive quantitative assay at the initiation of or shortly before treatment and at week 12 of therapy, (Class I, Level A).3

•For the diagnosis of acute hepatitis C, HCV RNA testing is required since HCV RNA appears before anti-HCV antibodies may be detectable.4

Decision Point 6: Counseling and Retesting and Other Testing as Appropriate 

Evidence not Sufficient; Recommendation to Include is Based on Expert Opinion

•Persons who use or inject illegal drugs should be advised: To stop using and injecting drugs; to enter and complete substance abuse treatment.5

•Persons who are at risk for sexually transmitted diseases should be advised: That the surest way to prevent the spread of HIV infection and other STDs is to have sex with only one uninfected partner or not to have sex at all; To use latex condoms correctly and every time to protect themselves and their partners from diseases.5

Decision Point 7: Initial Test for HCV: Comprehensive Metabolic Panel 

Strong Recommendation Based on Strong Evidence

•Laboratory monitoring should include measurement of the serum creatinine, and ALT levels, and HCV RNA by a sensitive assay at weeks 4, 12, and 24 of treatment, 4 to 12 week intervals thereafter, the end of treatment, and 24 weeks after stopping treatment.3

Decision Point 8: Initial Test for HCV: HCV Genotype 

Strong Recommendation Based on Strong Evidence

•HCV genotyping should be performed in all HCV-infected persons prior to interferon-based treatment in order to plan for the dose and duration of therapy and to estimate the likelihood of response (Class I, Level A).3

•The HCV genotype must be assessed prior to antiviral treatment initiation and will determine the dose of ribavirin and treatment decision.4

Decision Point 9: Initial Test for HCV: International Normalized Ratio 

Evidence not Sufficient; Recommendation to Include is Based on Expert Opinion

•International normalized ratio recommended at baseline (anti-HCV positive), pre-treatment, and as part of ongoing monitoring if patient exhibits signs and symptoms of liver disease.6

Decision Point 10: Initial Test for HCV: Complete Blood Count and Differential 

Strong Recommendation Based on Strong Evidence

•Complete Blood Count and Differential recommended at baseline (anti-HCV positive), pre-treatment, and at weeks 2 and 4 of treatment, 4 to 8 week intervals thereafter, 24 weeks post-treatment, and 12 months post-treatment.6

Decision Point 11: Initial Test for HCV: HIV Antibody 

Evidence not Sufficient; Recommendation to Include is Based on Expert Opinion

•Because of the high prevalence of HIV/HCV co-infection, and because the management of each infection can differ in dually-infected persons, all HIV-infected persons should be tested for HCV and all HCV-infected persons with HIV risk factors should be tested for HIV.3

Decision Point 12: Initial Test for HCV: HBV Surface Antigen 

Evidence not Sufficient; Recommendation to Include is Based on Expert Opinion

•Because dual infection is associated with worse prognosis than HCV infection alone and because the management of each virus can differ in dually infected persons, all HCV-infected persons with HBV risk factors should be tested for HBV.3

Decision Point 13: Administer HAV Vaccination if No Documented Immunity 

Evidence not Sufficient; Recommendation to Include is Based on Expert Opinion

•All persons with chronic HCV infection who lack antibodies to hepatitis A and B should be offered vaccination against these 2 viral infections (Class IIa, Level C).3

Decision Point 14: Administer HBV Vaccination if No Documented Immunity 

Evidence not Sufficient; Recommendation to Include is Based on Expert Opinion

•All persons with chronic HCV infection who lack antibodies to hepatitis A and B should be offered vaccination against these 2 viral infections (Class IIa, Level C).3

Decision Point 15: Conduct Brief Alcohol Screening and Intervention as Clinically Indicated 

Strong Recommendation Based on Strong Evidence

•All persons identified with HCV infection should receive a brief alcohol screening and intervention as clinically indicated, followed by referral to appropriate care and treatment services for HCV infection and related conditions (Strong Recommendation, Moderate Quality of Evidence).1

PIIS0016508513012857_gr1_lrg

References

Reprint requests Address requests for reprints to: Chair, Clinical Practice and Quality Management Committee, AGA National Office, 4930 Del Ray Avenue, Bethesda, Maryland 20814. e-mail:lclote@gastro.org; telephone: (301)-272-1188.

Conflicts of interest The authors disclose the following: Stuart C. Gordon has received grant/research support from Abbvie Pharmaceuticals, Bristol-Myers Squibb, Gilead Pharmaceuticals, GlaxoSmithKline, Intercept Pharmaceuticals, Merck, and Vertex Pharmaceuticals, is a consultant/adviser for Bristol-Myers Squibb, CVS Caremark, Gilead Pharmaceuticals, Merck, Novartis, and Vertex Pharmaceuticals, and is member on the Data Monitoring Board of Tibotec/Janssen. Mark D. Boldt is on the advisory board of Gilead and Janssen. Arthur Y. Kim is a consultant for Gilead Sciences and Abbvie Pharmaceuticals and has received research grants and support from Bristol-Myers Squibb. Joel V. Brill is a member of The American Association for the Study of Liver Diseases, American Gastroenterological Association, and American Medical Association-convened Physician Consortium for Performance Improvement® workgroup that developed the Hepatitis C Performance Measurement Set. Gary L. Davis is a member on the Data and Safety Monitoring Boards for Gilead and BMS. Ronald G. Nahass is a speaker for Merck and Vertex, completed clinical research for Merck, Gilead, Janssen, Abbvie Pharmaceuticals, and BMS and is on the advisory board for Janssen and Merck. The remaining authors disclose no conflicts.

PII: S0016-5085(13)01285-7

doi:10.1053/j.gastro.2013.09.007

© 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

Source

Daclatasvir: potential role in hepatitis C

Authors: Lee C

Published Date October 2013 Volume 2013:7 Pages 1223 - 1233

DOI: http://dx.doi.org/10.2147/DDDT.S40310

Received: 29 July 2013
Accepted: 29 August 2013
Published: 16 October 2013

Choongho Lee
College of Pharmacy, Dongguk University-Seoul, Goyang, Republic of Korea

Abstract: Chronic hepatitis C virus (HCV) infection is responsible for the development of liver cirrhosis and hepatocellular carcinoma. It has been a tremendous burden on global health care systems. With the advent of a number of new direct-acting and host-targeting antiviral agents, current interferon-a- and ribavirin-based HCV therapy has started to move towards an interferon-sparing or even interferon-free strategy. In this regard, a recently identified NS5A inhibitor, daclatasvir, showed a great promise in clinical trials as another new class of direct-acting anti-HCV therapeutics, with a distinct mechanism of action. In this review, a variety of preclinical as well as clinical proof-of-concept studies of daclatasvir, including the studies of its discovery, mechanism of action, viral resistance, and host polymorphism profiles are reviewed. In addition, a role of daclatasvir in the future therapy for HCV patients is discussed briefly.

Keywords: hepatitis C virus, nonstructural protein 5A, NS5A inhibitor, hepatitis C treatment

Read full article here (PDF)

FDA panel backs approval of new protease inhibitor for hepatitis C

By: ELIZABETH MECHCATIE, Family Practice News Digital Network

10/25/13  

SILVER SPRING, MD. – A Food and Drug Administration advisory panel unanimously supported the approval of the antiviral drug simeprevir as a treatment for chronic hepatitis C.

The approval was based on the highly favorable benefit-risk profile of the drug in studies that included sustained viral response rates of 79%-80% in phase III studies of patients with chronic HCV.

At a meeting on October 24, the FDA’s Antiviral Drugs Advisory Committee voted 19-0 that simeprevir, a hepatitis C virus (HCV) protease inhibitor, in combination with pegylated interferon and ribavirin (PR), be approved for the treatment of chronic hepatitis C genotype 1 (GT1) infection in adults with compensated liver disease, including cirrhosis, who are treatment-naive or have failed previous interferon-based therapy. The dosing proposed by the manufacturer, Janssen Pharmaceutical Co., is a 150-mg capsule once a day for 12 weeks, combined with PR for 24 weeks, in patients who have never been treated for HCV and for those who have relapsed on treatment. For patients who have not responded to previous treatments, PR is continued for 48 weeks.

The panel agreed that the risk-benefit profile was favorable, and with the once-daily dose, simeprevir was much easier to take than the first-generation protease inhibitors currently approved for treating chronic HCV, telaprevir and boceprevir, which are the current standard of care and require a total of 6-12 pills a day, taken at three times a day. Simeprevir inhibits HCV NS3/4A serine protease, which is "essential for viral replication," according to Janssen.

"We clearly need better drugs, and evidence is strong that this is a better drug," said panelist Dr. Curt Hagedorn, chief of the medicine service, Central Arkansas Veterans Healthcare Services, Little Rock.

"As someone who treats patients with chronic hepatitis C every day, this regimen represents a much simpler one and much safer" than currently available treatments, added panelist Dr. Marc Ghany, staff physician in the liver disease branch of the National Institute of Diabetes, Digestive and Kidney Diseases.

Panelists, however, urged Janssen to study more black patients in postmarketing trials, since black patients were greatly underrepresented in the studies but make up a large proportion of those infected with HCV in the United States. Postmarketing studies should also evaluate the drug in Hispanics, those coinfected with HIV, pediatric patients, patients with renal failure, and more patients with cirrhosis, they added.

The main safety issue discussed was the higher rates of rashes and photosensitivity reactions associated with treatment, which the FDA has proposed be included in the warnings and precautions section of the drug’s prescribing information, including a recommendation for patients to use sun protection measures while taking the drug. The panel agreed with the FDA and the manufacturer that before starting treatment, patients with HCV genotype 1a infections should be screened for the "Q80K" viral polymorphism – which is common in the United States and was associated with lower efficacy rates in the studies.

If approved, simeprevir will be the third HCV protease inhibitor approved in the United States for treating hepatitis C. In May 2011, boceprevir (Victrelis) and telaprevir (Incivek), which are also HCV NS3/4A protease inhibitors, were approved. In addition to the number of daily pills required, adverse events associated with these drugs include anemia and rash.

In three phase III studies of almost 1,200 patients most of whom were white, with chronic HCV genotype 1 infections, who had not been treated previously or had relapsed on previous treatment, simeprevir, 150 mg once a day for 12 weeks, combined with PR, followed by PR alone for 12 or 36 weeks (depending on the patient’s response), was compared with PR alone for 48 weeks (which included a placebo for the first 12 weeks). The primary efficacy endpoint was the sustained virologic response at 12 weeks (SVR 12), defined as HCV RNA that was undetectable or was detected at a level below 25 IU/mL 12 weeks after treatment was planned to end. (In the different arms of the studies, 40%-57% of the patients had HCV genotype/subtype 1a, and 43%-59% had 1b.)

In the two studies of 785 treatment-naive patients, 80% of those treated with simeprevir achieved an SVR12, compared with 50% of controls. The "on-treatment failure" rates (those who had detectable HCV RNA at the end of treatment) were 8% of those treated with simeprevir, compared with 33% of controls. The rates of viral relapse were 12% among those on simeprevir, compared with 22% of those on placebo.

In the third study of 393 relapsers, the SVR12 rate was 79% among those on simeprevir, compared with 36% among those on PR alone. Among those on simeprevir, 3% were on-treatment failures and 19% had a viral relapse, compared with 29% and 48%, respectively, of those on placebo.

In phase III studies, fatigue, headache, and influenzalike illness, associated with PR, were the most common adverse events. The only deaths reported were in three patients treated with simeprevir after they stopped taking the drug, but were not considered related to the drug. During the first 12 weeks of treatment, dyspnea was also higher among those on simeprevir (12% vs. 8%), but so far, the cause has not been determined, according to the FDA reviewer. Hyperbilirubinemia was also higher among those on simeprevir (49% vs. 26%), mostly grade 1 and 2 abnormalities.

In the first 12 weeks in the phase III studies, rashes (including photosensitivity) were reported in 28% of those on simeprevir, vs. 20% of those on PR only. Pruritus was also more common among those on simeprevir (22% vs. 15%); 1% of patients discontinued treatment because of a rash.

Janssen is investigating the appropriate dose in people of Eastern Asian descent. Exposure in these patients is higher, and rashes, photosensitivity, and other adverse events are increased with greater drug exposures, according to the FDA. A 100-mg daily dose of simeprevir has been approved in Japan (the only country where the drug has been approved to date). The drug is also being reviewed for approval in the European Union.

Among people with chronic HCV infections in the United States, genotype 1 is the most common, accounting for 75% of cases, according to the FDA.

The FDA usually follows the recommendations of its advisory panels and is expected to make a decision on this application by Nov. 27. Members of FDA panels have been cleared of conflicts related to the product under review; occasionally, a panelist is given a waiver, but not at this meeting.

emechcatie@frontlinemedcom.com

Source

Medscape Internal Medicine

Marrecca Fiore, Margaret Hamburg, MD
October 17, 2013

Editor's Note :
US Food and Drug Administration (FDA) Commissioner Margaret Hamburg, MD, spoke with Medscape during the recent National Health Research Forum in Washington, DC, and discussed clearing the hurdles to drug and device approvals, advancing personalized medicine, and smart spending to leverage scientific enterprise.

Medscape: Your panel today talked about "clearing the hurdles to a research and healthcare renaissance." Some researchers and clinicians see the FDA as a hurdle to getting new lifesaving medications and medical devices to patients. Can you discuss what the FDA is doing right now to streamline and speed up the drug and device approval process?

Dr. Hamburg: Sure. When you look at what is required to move an important discovery in science into a real-world product that patients and consumers want and need, obviously we play a critical role. We are responsible for reviewing the data to really examine critical questions about safety and efficacy. We see that as a clear value for patients and their families, and also for the industry sponsors of these products. Because if the product doesn't work, if it is going to cause problems, it is not in the industry's best interest either.

We need to all work together, and I think part of the discussion in the conference today was how important it is to have all the voices and perspectives represented around the table. FDA is one important player in that process, and we play a critical role because we sit in a position where we can look on one side and see what the unmet medical and public health needs are, and we can also see what is in the pipeline.

But we have an obligation to do our jobs as effectively and efficiently as possible. During my tenure as commissioner, I have worked hard to make sure that, number one, we are as engaged in the science as we can possibly be, and to make sure that we have people with the right scientific expertise and experience to appropriately review applications that come before us. More important, to engage with the scientific community early and often so that, as products are being developed, as new discoveries are moving through the pipeline, we help identify what kinds of data are going to be needed, what kinds of questions have to be asked and answered as part of the ultimate review process, and our ability to approve a drug to go into the marketplace. And we know that by working together in that way, we can actually speed the development process and the review process.

We also have to commit ourselves to making sure that our business processes are as efficient as possible so that we don't sit on applications, so that we return phone calls, so that we have the kind of mechanisms to hire the people that we need, train them properly, etc. We have focused very much on really strengthening our ability to do our job, but we see our job as part of a bigger mission to really advance biomedical product innovation.

Record Numbers of Drug and Device Approvals

Medscape: Correct me if I am wrong, but I believe you said that the FDA has actually been approving more drugs and devices than in the past.

Dr. Hamburg: In the past couple of years, we have had record numbers of new medical product approvals and, more important, we approve more drugs first. If you compare us with other countries, we approve new drugs more quickly. I think we are providing a critical and unique service to the American people.

We can always do better. We must do better, but I think one of the lessons from our panel today -- and certainly a lesson from my experience at FDA and working as a bench scientist and a healthcare provider -- is that we have to always recognize that real, sustainable progress doesn't happen by operating in a silo. We need this kind of partnership and coordination across all of the components and all of the stakeholders [in the approval process] to really make the difference we want to make.

Medscape: Turning to clinical trials, there are some who believe that the randomized, placebo-controlled trial is somewhat antiquated and not always the best method of gauging real-world results when it comes to new drugs and devices. How is the FDA working to improve the way it tests new products?

Dr. Hamburg: We are so far down that path that this question is almost irrelevant, to be honest. Obviously, the randomized controlled clinical trial is the absolute gold standard in terms of rigorous science and getting really solid answers. But there are lots of other ways to get robust scientific answers without using that, and there are many circumstances where you simply can't do a randomized controlled clinical trial for ethnical reasons or practical reasons. We look at [this kind of trial] as one tool in our toolbox, and we use many other strategies in terms of the kinds of clinical data that we will use for review.

We have also funded a lot of work in this area to really look at innovative clinical trial design, working with our academic partners and in some cases with industry. We see it as an area ripe for continuing collaboration and development of new strategies and approaches. But it is critically important, as we learn more and do more, that we become increasingly flexible and innovative in our approaches.

Advancing Personalized Medicine and Scientific Enterprise

Medscape: One of the FDA's science and research initiatives is to stimulate innovation, clinical trials, and personalized medicine. Personalized medicine and genomic medicine are becoming increasingly important in the treatment of diseases. Can you explain what is being done in this area?

Dr. Hamburg: As we learn a lot more about the underlying mechanisms of disease and the relationship of certain disease processes to certain genetic traits, we also understand that even within one disease category, responsiveness to certain treatments may be different depending on certain genetic traits of the individual -- or in the case of oncology, the tumor.

We have an opportunity now to really deepen these understandings and build on them in terms of the therapies that are developed and how they are used, and that requires some new approaches in terms of the types of therapies that are being developed and the use of diagnostics that are a companion to therapy so that you can identify the subsets of responders and nonresponders. We are very deeply immersed in these activities. We have seen a number of really exciting approvals in recent years linking the diagnostic with the therapeutic, and we have seen some dramatic translations of new scientific understandings into products for people based on this approach. We are going to see more and more as time goes on.

Medscape: Finally, what is on your wish list for the future in terms of research and research funding of drugs and devices?

Dr. Hamburg: When we look at the sort of scientific enterprise overall, the understanding and investment in regulatory science have not been adequate. I think that if we really want to be able to deliver the biomedical products that the public wants and deserves, we have to address that. My wish list would be that we at FDA could get additional resources to help fund research in critical areas that will enable us to apply the advances in science and technology more effectively to the drug development process and the drug review process, whether it is genomics or bioinformatics, bioimaging, new clinical trial designs, etc.

There is so much opportunity, but it hasn't been fully developed. We have started some centers of excellence for regulatory science in academic centers, and it has been very, very productive and very valuable. We have created new partnerships, including precompetitive collaborative research with industry academia and government, including the National Institutes of Health. All of that has demonstrated real benefit in helping to move research and development forward and getting some of these exciting new understandings of disease and health out to people in terms of new products. But it is not enough.

We really need to capitalize on the opportunities [presented at the conference] today -- that would be my wish list. Of course, the reality as we know it is that dollars are constricting, so we have to be as smart as possible about leveraging resources. Part of what we talked about in the conference today was that we are going to have to make some hard choices. We are going to have to think about how we spend limited dollars, but I think that we really need to recognize that this arena of regulatory science is so key, and that it has been the weakest link in the chain of science that is necessary to truly realize the potential of science today.

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Can liver transplantation provide the statistical cure?

Liver Transplantation

Accepted Article (Accepted, unedited articles published online and citable. The final edited and typeset version of record will appear in future.)

Original Article

A. Cucchetti M.D1,*, A. Vitale M.D., Ph.D.2, M. Cescon M.D. Ph.D.1, M. Gambato MD3, L. Maroni M.D.1, M. Ravaioli M.D. Ph.D.1, G. Ercolani M.D.1, P. Burra M.D., Ph.D.3, U. Cillo M.D., Ph.D.2, A.D. Pinna M.D. Ph.D.1

DOI: 10.1002/lt.23783

Publication History
Accepted manuscript online: 26 OCT 2013 04:38AM EST
Manuscript Accepted: 19 OCT 2013
Manuscript Revised: 16 SEP 2013
Manuscript Received: 25 JUN 2013

©2013. American Association for the Study of Liver Diseases

Keywords:Liver transplantation; cure model; relative survival; excess hazard rate

ABSTRACT

Liver transplantation (LT) represents the only chance of long-term survival for patients with end-stage liver disease. When the mortality among transplanted patients returns to the same level as in the general population, they can be considered “statistically cured”. However, cure models in the setting of LT have never been applied. Data from 1371 adult patients, undergoing a first LT between January 1999 and December 2012 at two Italian centers, were reviewed in order to establish probabilities of being cured by LT. A parametric Weibull model was applied to compare mortality after LT to that expected in the general population, matched by sex and age. The observed 3-, 5- and 10-year overall survival after LT was 77.8%, 73.3% and 65.6%, respectively, and did not differ between the two centers (P=0.366). The cure fraction for the entire study population was 63.4% (95%CI: 52.6%–72.0%) and the time-to-cure was 10 years with 90% of confidence level. The best cure fraction was observed for younger non-hepatitis C (HCV) recipients with favorable donor-recipient match, namely low Donor-Model for End-stage Liver Disease (D-MELD) scores (90.1%); conversely, the lowest probability was observed in elderly HCV recipients with high D-MELD scores (34.6%). The time-to-cure was 6.22 years for non-HCV patients and 14.78 years for HCV patients. Median survival of “uncured” patients was 2.29 years. Among uncured recipients, the longest survival was observed for younger patients (7.31 years). In conclusion, we provide here a new clinical measure in the LT scenario that suggests that survival after transplantation can approximate that of general population, providing the “statistical cure”. Liver Transpl , 2013. © 2013 AASLD.

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Alcoholism is a complicating factor for women with hepatitis C

By Tele management

Alcohol

TeleManagement) Women with hepatitis C lose survival advantage over men if they drink heavily.
Hepatitis C is a chronic infection of the liver which is passed on through contaminated blood and often linked with drug use. It sometimes leads to severe liver damage and liver cancer. Previous research has suggested that hepatitis C progresses more slowly among women, giving them a survival advantage. Drinking, to the point of alcoholism, on the other hand, worsens the outcome.

Researchers for the National Institute on Alcohol Abuse and Alcoholism put together these trends to look at the outcome for women with both hepatitis C and alcoholism. They analyzed 132,468 deaths related to hepatitis C or alcoholism. Women with hepatitis C who were not heavy drinkers died at an average age of 61. Those women with both hepatitis C and alcoholism died at an average age of 49. For men, the corresponding average ages at death were 55 and 50 years. Therefore, alcoholism wipes out the gender advantage women have over men when it comes to survival from hepatitis C. The researchers admit the study has one limitation – alcoholism often precludes access to treatment for hepatitis C because those affected are less likely to benefit. This may be a contributing factor to the lower survival rates seen when hepatitis C and alcoholism are combined.

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