January 9, 2014

Am J Phys Med Rehabil. 2014 Jan 6. [Epub ahead of print]

Loria A, Doyle K, Weinstein AA, Winter P, Escheik C, Price J, Wang L, Birerdinc A, Baranova A, Gerber L, Younossi ZM.

Abstract

OBJECTIVE: The aim of this study was to assess whether physical performance correlates with metabolic and inflammatory measures in research subjects with chronic liver disease.

DESIGN: This is a prospective, descriptive cohort study correlating performance on a 6-min walk test with cardiorespiratory variables, metabolic measures (glucose [GLU], C-peptide insulin, and lipids), liver enzymes (aspartate aminotransferase and alanine aminotransferase), and the proinflammatory cytokine interleukin-8 (IL-8).

RESULTS: This study enrolled 51 subjects (18 women) with chronic liver disease: 41% (n = 21) with nonalcoholic fatty liver disease and 59% (n = 30) with hepatitis C virus. Age, resting heart rate, and fasting GLU correlated significantly with distance walked (P's < 0.05). First quartile "poor performers" (n = 14) and fourth quartile "high performers" (n = 14) showed differences in age, sex, fasting GLU, and IL-8 level (P's < 0.05). Combining the number of abnormal serum values (IL-8, C-peptide insulin, GLU, aspartate aminotransferase, alanine aminotransferase, high-density lipoprotein, triglyceride, and total cholesterol) did not correlate with distance walked (P > 0.90). However, in multiple regression analysis, a model that included sex, age, resting heart rate, IL-8 level, and fasting GLU level explained approximately 39% of the variance in the distance walked during the test.

CONCLUSIONS: Older age, female sex, abnormal levels of the proinflammatory cytokine IL-8, abnormalities of GLU metabolism, and high resting heart rate are associated with poor physical performance in subjects with chronic liver disease. Poor physical performance is associated with physiologic, metabolic, and inflammatory abnormalities in subjects with nonalcoholic fatty liver disease and hepatitis C virus.

PMID: 24398583 PubMed - as supplied by publisher]

Source

Baby Boomers and the Hepatitis C Boom

Annals of Emergency Medicine
Volume 62, Issue 6 , Pages A19-A21, December 2013

Ryan L. Nave (Special Contributor to Annals News & Perspective)

Section editor: Truman J. Milling, Jr, MD

It didn't take long after rolling out a new screening program for emergency physicians at the University of Alabama at Birmingham (UAB) to realize the scope and complexity of what has been called a silent killer for baby boomers: hepatitis C.

“We had previously estimated that somewhere between 3% and 5% of persons born between 1945 and 1965, who were unaware of their hepatitis C status, would be hepatitis C antibody positive,” said James Galbraith, MD, an emergency physician at UAB.

As it turned out, the prevalence was much, much higher than anyone at UAB had expected. After screening 40 baby-boomer patients that first day, 6 results were antibody positive for hepatitis C, a blood-borne viral disease that attacks the liver but remains dormant in the body for decades before symptoms appear, typically in the form of cirrhosis, liver disease, or liver cancer.

The 76 million people born between 1945 and 1965—also known as baby boomers—are especially at risk, accounting for three quarters of all hepatitis C infections in the United States. The crisis so alarmed health officials that it prompted the US Preventive Services Task Force in 2012 to recommend that all baby boomers be screened once for the disease.

The initial higher-than-anticipated prevalence rates caused some of the emergency physicians at UAB to believe the results might be a fluke, but these continued into the next days and weeks. As of October 1, the screening program's prevalence rate of approximately 13.5% remained unchanged. In the first 2 weeks after commencing the tests, UAB tested 524 baby boomers, and 70 of those patients' results were antibody positive for hepatitis C, Dr. Galbraith said.

With numbers like that, the department is on course to screen 15,000 patients in the first year. So far, Dr. Galbraith said the department is doing fine managing the testing itself, but he's concerned about looming challenges.

“We're really trying to revise what we're doing because we were estimating somewhere between 300 and 500 [hepatitis C–positive patients] identified in the first year, and now we're talking about 1,500. The benefits to screening are lost if you're not assisting patients and getting them linked into care,” Dr. Galbraith said.

He added: “Hepatitis C is a treatable and increasingly curable disease that disproportionately affects this population. So the clock is ticking for this baby boomer generation to get them into care and possibly even curative treatment.”

The Root of the Problem 

According to Centers for Disease Control and Prevention (CDC) estimates, about 3.2 million people in the United States have chronic hepatitis C infection. Present and past injection drug users are most at risk for the infection, as are people with HIV—10% to 15% of whom are coinfected with hepatitis C—and people who received blood transfusions before 1992 when hepatitis C screening became widely available.

Infection rates for hepatitis peaked in the mid-1970s, around the time injection drug use in the United States was also at its highest levels. Around 1960, hepatitis rates increased even though hepatitis C was then known only as hepatitis non-A non-B. By the early 1990s, injection drug use and transfusion-related transmissions experienced steep declines. Since then, hepatitis C infection rates have decreased 90%, data show.

In the 2 decades since, many of those individuals who were at the greatest risk during the height of the hepatitis C infection may have stopped using injection drugs or simply forgotten about a transfusion they received during a routine surgery such as a cesarean section and do not realize they should be screened for hepatitis C.

CDC data also show that for every 100 people infected with hepatitis C, somewhere between 5 and 20 will develop cirrhosis during a 2- to 3-decade period, and between 1 and 5 will die from cirrhosis or liver cancer. One-time screening of all baby boomers could result in identifying 800,000 people with hepatitis C, the CDC said.

In August 2012, the CDC published “Recommendations for the Identification of Chronic Hepatitis C Virus Infection Among Persons Born During 1945-1965” in the agency's Morbidity and Mortality Weekly Report, which helped sound the alarm.

“Hepatitis C virus (HCV) is an increasing cause of morbidity and mortality in the United States. Many of the 2.7 [to] 3.9 million persons living with hepatitis C virus infection are unaware they are infected and do not receive care (e.g., education, counseling, and medical monitoring) and treatment. CDC estimates that although persons born during 1945 [to] 1965 comprise an estimated 27% of the population, they account for approximately three fourths of all hepatitis C virus infections in the United States, 73% of hepatitis C virus–associated mortality, and are at greatest risk for hepatocellular carcinoma and other (hepatitis C)–related liver disease,” the report states.

Additionally, the CDC said that with the advent of new therapies that can halt disease progression and provide a virologic cure in most persons, targeted testing and linkage to care for infected persons in this birth cohort is expected to reduce hepatitis C virus–related morbidity and mortality.

John W. Ward, MD, director of the CDC's Division of Viral Hepatitis, said, “A major priority for hepatitis prevention is screening to identify persons living with chronic hepatitis B and hepatitis C and linking them to care to reduce the disease and death from chronic infection.”

In 2012, Congress directed $10 million to Dr. Ward's division from the Prevention and Public Health Fund, part of the Patient Protection and Affordable Care Act, to improve testing for hepatitis B and C. More than 150 providers applied 30 funding awards for specialized screening of foreign-born populations and injection drug users and at federally qualified health centers.

Separately, UAB received funding from the CDC Foundation's Viral Hepatitis Action Coalition to screen 8,000 baby boomers for hepatitis C for 1 year. The screen itself involves a polymerase chain reaction test (patients may opt out of the screen, but that is rare) performed on blood already drawn. And even though UAB may ultimately screen more patients than physicians planned for, the paying for the tests is only one part of the equation.

“A lot of these baby boomers who ultimately need treatment for hepatitis C infection…also have other comorbid conditions that need to be treated just to make them able to tolerate the regimens for hepatitis C treatment; you know: things like diabetes, high blood pressure,” Dr. Galbraith said. “Approximately 50% of patients that we're diagnosing have publicly funded insurances like Medicaid, indigent-care insurances, or are uninsured, and that becomes a real challenge in trying to get these individuals linked into care.”

Learning From Experience 

Emergency departments are good for diagnosing problems but are not the best option for providing long-term treatment. At UAB, that's where the hospital's 1917 Clinic comes in. The clinic, which served almost 2,000 patients in 2012, is Alabama's largest HIV health care facility. A few years ago, the clinic expanded its services to include hepatitis C testing.

Ricardo Franco, MD, a member of the 1917 Clinic's staff said the hepatitis C screening program attempts to use a similar model for care as the clinic. “Many of them have the emergency room as the only source to have health care access, and not being insured, that probably favors a life trajectory of not really paying attention to health expenses,” Dr. Franco said.

Dr. Galbraith, Dr. Franco's colleague at UAB, said data suggest that hepatitis C affects men more than women and disproportionately minorities and the uninsured. Blacks have hepatitis C infection rates twice that of the general population. Information from CDC in 2012 shows that between 2000 and 2011, the rate of hepatitis C among blacks increased by 27.3%; among Hispanics, by 21.4%. Also, American Indian/Alaska natives were doubly likely to develop a case of hepatitis C compared with the white population in 2011.

Corinna Dan, RN, MPH, a viral hepatitis policy advisor with the US Department of Health and Human Services' Office of HIV/AIDS and Infectious Disease Policy, said culture could sometimes be a barrier to treatment in minority communities. “There are many challenges, including very low awareness among communities and the providers who serve them, stigma related to having hepatitis C and the behaviors that most often lead to exposure—ie, injection drug use—[and] low rates of health insurance coverage, as well as limited access to health care providers who are trained to identify individuals at risk, manage, and treat chronic hepatitis C infection. An additional challenge in the African American community is that the previously available treatment for hepatitis C was not as effective in eliminating the virus in African Americans as it was for other racial and ethnic groups. This led to people deferring screening or not following up on referral to care because there was a sense that there was no treatment for them,” Ms. Dan wrote in an e-mail.

In addition to the limited infrastructure that exists for hepatitis C screening in general, lack of public education of the disease presents an additional barrier. At the same time, though, she sees opportunities. “There is very low public awareness of this condition, but there are more materials available now than there have been in the past, including some developed specifically for minority communities. There has not historically been a large investment in hepatitis C testing by public health entities; however, with the [US Preventive Services Task Force] screening recommendation now a “B” grade, screening will be covered for individuals with health insurance as a preventive health service free of cost sharing or copay under the Affordable Care Act.” She added, “The challenge we are faced with is educating community members to request the test and health care providers to recommend the test.”

Safety Net 

Ms. Dan, of the US Department of Health and Human Services, said that a variety of strategies should be developed to increase awareness of hepatitis C and encourage people to be tested for the infection, and that EDs “can be part of the solution.”

“We are working across government to increase awareness of and appropriate screening for hepatitis C, including working with colleagues at the Health Resources and Services Administration, which supports many safety net providers, including community health centers and hospitals,” she said.

Dr. Galbraith is in agreement. “We are the safety net for our communities and, to me, if you can do some of these screenings, which are burdensome and costly, if you can find ways to cover the costs, and make these things happen in the background without disturbing the other competing priorities we have in the emergency department, then we're doing a good service not just for our individual patients but for our community.”

Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www.icmje.org). The author has stated that no such relationships exist.

The views expressed in News and Perspective are those of the authors, and do not reflect the views and opinions of the American College of Emergency Physicians or the editorial board of Annals of Emergency Medicine.

PII: S0196-0644(13)01487-X

doi:10.1016/j.annemergmed.2013.10.013

© 2013 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.

Source

Citations Highlight Promising New Drugs for Hepatitis C Infection

08 Jan 2014
David Sharp


REUTERSAly-Song-3

The U.S. Centers for Disease Control and Prevention has recently revised its guidance on testing for infection with hepatitis C virus (HCV). Testing for anti-HCV, recommended for known at-risk groups for the past 15 years (and, in 2012, suggested as routine in the birth cohort 1945-65, the so-called “baby boomers”) does not distinguish between past and ongoing infection. The latest guidance includes tests for HCV RNA; these tests do make the distinction. Another reason for the revision is “significant advances in the development of antiviral agents with improved efficacy against HCV” (MMWR 62[18]: 357-61, 2013). Drawing on exclusive citation data from Thomson Reuters Web of Science, a new Top Ten list provides the opportunity for an update on those agents.

HCV infection is a serious public-health issue. World Health Organization global estimates include 150 million people with chronic HCV infection and 350,000 deaths from HCV-related liver disease and 3 to 4 million new infections annually. Many cases remain undiagnosed; there is currently no vaccine; and available treatments are not ideal. The six known HCV genotypes can respond differently; a mainstay of therapy has been interferon, a tricky drug to manage; and about 60% of patients with HCV genotype 1 infection are not cured by up to 48 weeks of interferon plus ribavirin (J.G. McHutchison et al,  New Engl. J. Med., 361[6]: 580-93, 2009). When ScienceWatch last covered the therapeutic options, the best on offer seemed to be a combination of polyethyleneglycolated interferon (PEG interferon) and the antiviral agent ribavirin. The picture has recently been changing, and rapidly, with the development of compounds that act more directly on HCV. The two current front-runners in terms of both clinical trial activity and publications and citations are boceprevir and telaprevir, still given in combination with the former dual therapy, but there is huge interest in second-generation candidates (vaniprevir, sofosbuvir and MK-5172, to name but a few).

Read the full ScienceWatch article to see the Top Ten list and to find out more about developments taking place in this therapeutic area.

Continue reading >>

Clin Infect Dis. (2014)doi: 10.1093/cid/ciu012

First published online: January 6, 2014

This article is Open Access

Andrew Hill1, Saye Khoo1, Joe Fortunak2, Bryony Simmons3, Nathan Ford4

1 Department of Pharmacology and Therapeutics, Liverpool University, UK
2 Chemistry and Pharmaceutical Sciences, Howard University, Washington, DC, USA
3 Imperial College London, London, UK
4 Centre for Disease Epidemiology and Research, University of Cape Town, South Africa

Address for correspondence: Dr Andrew M Hill PhD, Senior Visiting Research Fellow, Department
of Pharmacology and Therapeutics, University of Liverpool, 70 Pembroke Place, Liverpool L69 3GF,
United Kingdom. Email: microhaart@aol.com
 
Summary: Large-scale manufacture of treatment to cure Hepatitis C is feasible, with target prices of US$100-250 per 12 week treatment course. These low prices could make widespread access to
HCV treatment in low and middle income countries a realistic goal.

Abstract

Background: Several combinations of two or three Direct Acting Antivirals (DAAs) can cure HCV in
the majority of treatment-naïve patients. DAAs for HCV infection have similar mechanisms of action
and chemical structures to antiretrovirals for HIV infection. Generic antiretrovirals are currently
manufactured at very low prices, to treat 10 million people with HIV/AIDS in developing countries.

Methods: Four HCV DAAs, currently either in Phase III development or recent approval (daclatasvir,
sofosbuvir, simeprevir, faldaprevir) and ribavirin were classified by chemical structure, molecular
weight, total daily dose and complexity of synthesis. The likely range of manufacturing costs per
gram of DAA were then projected as formulated product cost, based upon treating a minimum of
one million patients annually (to arrive at volume demand) combined with an analysis of the
complexity of synthesis and a 40% margin for formulation. Projections were then compared with
actual costs of antiretrovirals with similar structures.

Results: Minimum manufacturing costs of antiretrovirals were US$0.2-2.1/g. The complexity of
chemical synthesis for HCV DAAs was ranked from lowest to highest: ribavirin, daclatasvir,
sofosbuvir, faldaprevir and simeprevir. Predicted manufacturing costs for 12-week courses of HCV
DAAs were: US$21-63 for ribavirin, US$10-30 for daclatasvir, US$68-136 for sofosbuvir, US$100-
210 for faldaprevir, and US$130-270 for simeprevir.

Conclusions: Within the next 15 years, large-scale manufacture of two or three drug combinations of  HCV DAAs is feasible, with minimum target prices of US$100-250 per 12 week treatment course.  These low prices could make widespread access to HCV treatment in low and middle income  countries a realistic conclusion.

Introduction

Worldwide, over 185 million people are infected with Hepatitis C Virus (HCV), with up to 500,000 HCV-related deaths per year.1,2 The vast majority of these patients are left untreated, with treatment rates ranging from 3.5% in Europe to 21% in the US.3,4

In comparison, approximately 35.3 million are infected with Human Immunodeficiency Virus (HIV), with 1.6 million HIV-related deaths per year.5 The vast majority of these infections and deaths are in resource-limited settings. Due to remarkable progress in reducing costs of treatment, over ten million patients are now on antiretroviral (ARV) regimens in low- and middle-income countries.5

People with Hepatitis C infection can be cured using modern treatment, but at a very high cost. The US launch prices for 12 weeks treatment with simeprevir and sofosbuvir, two newly approved drugs, are US$66,000 and US$84,000, respectively.6 In low and middle income countries, access to HCV treatment is extremely limited, mainly because of the complexity of patient management and high costs.7 Of the twenty countries with the largest HCV epidemics, twelve are classified as low or lower-middle income (Table 1). For widespread treatment of HCV in developing countries to become feasible, we will need short-course antiviral treatment available at very low costs and with minimal diagnostic support.

Capture

Recently, a number of direct acting antivirals (DAAs) in Phase 2 or 3 development have shown sustained virological response (SVR) rates of up to 100% in non-cirrhotic patients and, promisingly, high SVR rates in people with advanced liver disease or previous null response (Table 2). The approval of such drugs will likely see DAA combinations replace interferon-based regimens as the new standard of care.18 Success of treatment often depends on genotype and while the majority of results are from clinical trials carried out on patients infected with the HCV-1 genotype, encouraging results are emerging for the treatment of both HCV-2 and HCV-3 (Table 2).

Capture2

DAAs for HCV infection have similar mechanisms of action and chemical structures to antiretrovirals currently in use for the treatment of HIV. These drugs are also similarly intended for oral delivery using relatively uncomplicated formulation technologies. Over the last two decades, generic competition, increased purchase volumes, and improvements in manufacturing processes (both API and formulation) have driven the cost of HIV antiretroviral treatment down by over 99%, with standard triple therapy now costing as little as US$60 per patient per year.19

These prices could not have been imagined when triple antiretroviral drug combinations were introduced at over US$10,000 per patient/year in the late 1990s.7 Following the important precedent set by access to treatment for HIV infection, the aim of this analysis was to estimate the minimum cost of HCV treatment, assuming the same strategic market dynamics as used to supply antiretrovirals to people with HIV/AIDS in developing countries.

Methods

In this analysis, the molecular structures of HCV DAAs were compared with their closest analogues in the treatment of HIV. We evaluated the likely routes of manufacturing as published by the originator companies and assumed a volume demand based on 1-5 million patients per year to arrive at approximate costs of DAA active pharmaceutical ingredients (APIs). We then added on a 40% margin for finished production manufacturing (formulation) to arrive at a projected cost of therapy.

The purpose of this analysis is to logically speculate whether DAAs can be provided for millions of people at a reasonable cost. The analysis is not meant to be exact or to arrive at a “most likely optimised cost” for any individual or combination DAA therapy. Very little information is presently available to estimate actual commercial formulation costs for DAAs. These DAAs are all delivered orally using conventional technologies. Projected API costs for these DAAs range from US$1,400- 21,000/kg; as such the very high relative costs of API would justify a 40% increment as a reasonable add-on for estimating cost of the finished dosage form.

The minimum treatment costs of comparator HIV antiretrovirals were calculated using the lowest prices reported by manufacturers to Médecins Sans Frontières in 2012.19 Minimum costs per gram of ARVs ranged from US$0.20 to US$0.90/g for nucleoside analogues, US$0.50/g for nucleotide analogues, and US$0.70-2.10/g for protease inhibitors (Table 3).

Capture3

Four HCV DAAs were included in this study: daclatasvir (Phase III), sofosbuvir (approved December 2013), faldaprevir (Phase III), and simeprevir (approved November 2013). Ribavirin, already available as a generic, was also included in this analysis due to its likely inclusion in future drug regimens. Using the most likely daily dosage identified from clinical trials, the total drug requirement for each DAA was calculated for a 12 week course of each HCV DAA. In order to estimate the manufacturing cost of each HCV DAA, current routes of synthesis and critical cost-limiting raw materials were taken from the patent literature. In an alternative comparison, each compound was matched to the closest equivalent HIV ARV based on structural similarity.

Production costs per gram of HCV DAA were assumed to be 1-10 times higher than the equivalent HIV ARV dependant on the complexity of chemical synthesis. Complexity was assessed by identifying the most likely cost-limiting intermediates for the synthesis of each DAA. Additional considerations included ease and number of steps of manufacture and availability and cost of starting materials. Using this estimate for the production cost per gram of drug together with the total drug requirement, an estimate for the minimum cost of a 12 week course of treatment with each HCV DAA was calculated. These costs were used to provide estimates for the production costs of 2- or 3-drug combination therapy based on the combinations currently being investigated in clinical trials (Table 2)

Results

Based on molecular weight, chemical structure, class, and dose, the HIV ARV most comparable to each HCV DAA were as follows: zidovudine to ribavirin, atazanavir to daclatasvir, tenofovir and stavudine to sofosbuvir, darunavir to faldaprevir, and lopinavir to simeprevir. Table 4 shows the HCV DAA and most comparable HIV antiretroviral as well as the likely cost limiting raw materials in production. A summary of the estimated costs per person for a 12 week course of each HCV DAA is shown in Table 5

5

Ribavirin With a daily dose of 1000-1200mg dependent on patient weight, a 12-week course of treatment with ribavirin will require between 84.0 and 100.8 grams of API. This results in a range of demand between 84 and 504 metric tonnes of API to treat between 1-5 million patients. Ribavirin is a nucleoside analogue with a molecular weight of 244g/mol. Based on this and the chemical formula (Table 3), zidovudine was considered to be the closest equivalent HIV relative of ribavirin (also a nucleoside analogue with molecular weight 267g/mol). Analysis revealed that ribavirin has a relatively simple chemical synthesis.20 Using zidovudine alongside knowledge of the current costs of ribavirin, production costs were estimated to lie between US$0.26 and US$0.41 per gram, giving potential costs for a 12-week course of ribavirin of US$34-48 for the dose of 1000mg per day, and US$41-58 for the dose of 1200mg/day.

Daclatasvir At the dose of 60mg/day, a 12-week course of treatment would require 5.0 grams of daclatasvir API. Daclatasvir is a NS5A inhibitor with molecular weight 739g/mol. Treating 1-5 million patients with daclatasvir would require 5-25 metric tonnes of API. Daclatasvir was deemed most structurally comparable to atazanavir, a protease inhibitor with molecular weight 705g/mol (Table 3). Daclatasvir has a straightforward synthesis with the cost-limiting intermediate being the substituted biphenyl compound shown (Table 5).21,22 There is wide availability of cheap starting materials to synthesise the side-chains of daclatasvir. The estimated production costs of daclatasvir finished product are between US$2 and US$6 per gram. At a daily dose of 60mg, the estimated production costs for a 12-week course of treatment were between US$10-US$30.

Sofosbuvir Delivered at a 400 mg daily dose, a 12-week course of treatment with sofosbuvir will require 33.6 grams of API. This results in a range of API demand between 33.6 and 168 metric tonnes to treat 1-5 million patients. With a molecular weight of 529g/mol and chemical formula of C22H29FN3O9P, sofosbuvir was considered most structurally comparable to tenofovir, with a molecular weight of 636g/mol and chemical formula C23H34N5O14P (Table 3). The cost-limiting raw material/intermediate for the synthesis of sofosbuvir API is the 2’-fluoro-2’-methylfuranose intermediate (Table 5). 23,24,25 Although a number of approved drugs have similar structures, the presence of both a methyl and a fluoro substituent at the 2’ position makes this intermediate cost-limiting. We have estimated API production costs for sofosbuvir between US$2 and US$4 per gram; sofosbuvir is considered most closely analogous in cost to the HIV drug stavudine, which is relatively expensive in terms of manufacturing costs per gram. An estimated cost for 12 weeks of treatment with sofosbuvir API is US$68-136.

Faldaprevir At a daily dose of 120 mg, 10.1 grams of faldaprevir API will provide a 12-week course of treatment. Treating 1-5 million patients with Faldepravir would require 10.1-50.5 metric tonnes of API. Faldaprevir is a protease inhibitor with a molecular weight of 870g and chemical formula of C40H49BrN6O9S (Table 3). As a result of this high molecular weight and complicated chemical structure darunavir was deemed the most cost-comparable with faldaprevir. Faldaprevir manufacture requires a tetra-substituted quinoline and a vinyl-cyclopropane amino acid as raw materials for the synthesis of the API (Table 5).25,26 Due to the difficult synthesis, estimated production costs of US$10-21 per gram were applied. Accordingly, a 12-week course of treatment with faldaprevir could cost between US$100 and US$210.

Simeprevir At a daily dose of 150 mg, a course of treatment with simeprevir would require 13 grams of simeprevir API. Treating 1-5 million patients with Simepravir would require 13-65 tonnes of API. In terms of class, molecular weight and chemical structure, lopinavir/r was considered the equivalent HIV ARV of simeprevir, although atazanavir was included in comparing cost estimates (Table 3). Simeprevir is a medium-ring macrocycle that utilises a ring-closing metathesis reaction in the late stages of API manufacturing, which is challenging (Table 5). Novel raw materials entered into the synthesis include a tetra-substituted quinoline and the same vinyl-cyclopropane amino acid as used  in the synthesis of faldaprevir.27 Production costs were estimated at US$10 to US$21 per gram, giving an estimated cost of treatment of US$130-270 for 12 weeks.

Combination therapies Table 6 shows the estimated prices of combination therapy based on the DAA drug prices calculated in this analysis. Using the minimum costs, a 12-week course of treatment with daclatasvir and sofosbuvir could cost a minimum of US$78 per person. A treatment with sofosbuvir and simeprevir could cost US$198 for 12 weeks with the addition of ribavirin increasing this cost to US$219 per person. For some patients or some regimens, a 24-week treatment might be necessary, doubling treatment costs.

6

Discussion

Fifteen years ago, universal access to antiretroviral therapy for HIV/AIDS in developing countries was considered too complex and expensive to be feasible. With the invention of effective, simple therapy, a market was created for generic competition that in turn made treatment affordable, and along with the associated international funding, treatment scale up became possible.28 The situation of HCV treatment today is reminiscent of treatment for HIV/AIDS in the year 2000.

Our analysis suggests that 2 or 3 drug combinations of interferon-free HCV treatments could cost US$100-250 for a 12 week course of treatment. These low prices coupled with the high SVR rates established in several trials shows the potential for large-scale, low cost HCV treatment in developing countries, with the potential to repeat the model of low-cost HIV treatment that has benefitted millions of people. This model of treatment is based on simplified, standardised treatment approaches using tolerable, easy-to-administer regimens that are supportive of task shifting (care delivery by lesser trained health staff) and good patient adherence, and could be facilitated by widespread access to oral, short-course DAA therapy in low income countries.29

The cost of production of HIV antiretrovirals has fallen progressively over the past decade through increased market competition, increased volumes, and efficiencies in manufacturing processes. The  Clinton Health Access Initiative pioneered purchasing from quality-assured generic pharmaceutical manufacturers in India and raw material manufacturers in China to ensure the lowest sustainable costs for some antiretrovirals, lowering prices dramatically.30 Our estimated unit costs of HCV DAAs per gram are still far higher than the current costs of HIV antiretrovirals, and it could be assumed that the cost of HCV DAAs may further decrease over time through process optimisation and the cheaper sourcing of raw materials as volume demand drives competition and process efficiencies.

We have been conservative in our estimations versus the history of costs for HIV drug production. API syntheses begin with raw materials of rather simple structure that are combined in a specific and modular fashion to build the more complex structures of drugs. When a commercial market already exists for these raw materials, their contribution to cost is rather modest. When raw materials with no previous commercial demand are used, these can contribute very substantially to cost. Efavirenz, an HIV-1 reverse transcriptase inhibitor, provides an illustration of this. Cyclopropylacetylene (CPA) is a raw material for the synthesis of efavirenz. During human clinical trials, when the demand for CPA was only a few metric tonnes, CPA cost was US$800-1350/kg. When the drug was approved (1998) and demand for CPA was about 50 tonnes per year, the price of CPA had fallen to US$300-350/kg. Today, with a global demand for efavirenz of over 800 tonnes/year, CPA can be purchased for US$50-60/kg. Efavirenz was launched in 1998 at an API cost of $1800/kg. The current best cost for the API is about $120/kg from Indian generic suppliers.

The DAA molecules in this analysis each contain at least one novel raw material that will be expensive in the early phases of commercial introduction. Similar to the reductions in the cost of efavirenz, the estimated costs in this analysis can only be justified if we can guarantee the eventual procurement of large orders. With the DAAs investigated in this study, twelve weeks treatment for one million patients would require between 5 and 34 metric tonnes of API, with ribavirin requiring between 84 and 101 tonnes of active ingredient. Treatment for only a fraction of the 185 million people infected with HCV could ensure order sizes in a similar region to HIV antiretrovirals.

With the introduction of these new HCV DAAs, the methods used to diagnose and monitor HCV are likely to be greatly simplified.31 In order to ensure widespread treatment, the costs of diagnostic and monitoring tests will also need to fall. In the same way that the cost of HIV treatment has decreased, the cost of HIV diagnostics and monitoring has rapidly declined over the last few decades with commercial HIV RNA tests now costing less than US$2 per test.32

There are several limitations with this analysis. Firstly, in order to calculate more precise costs, more detailed analysis of the API and formulation processes for production will be necessary. Very little specific information is currently available about formulations of the DAAs. However, all of the DAAs are for oral delivery and – to the best available knowledge – use relatively common drug release technologies. This is in parallel with the formulation of ARVs. Given this, we applied a 40% conversion cost of API to finished product, noting that this figure is not exceeded for any of the large-scale ARV combinations being marketed. Secondly, access to the HCV DAAs at minimum prices in developing countries will strongly depend on the level of enforcement of patent restrictions. These price estimates are based on the previous experience with production of ARVs for HIV treatment which assumes market competition through generic manufacture. Legal mechanisms such as voluntary or compulsory licenses may be needed to overcome patent barriers and stimulate such competition. Patents for daclatasvir,33 sofosbuvir,34 faldaprevir,35,36 and simeprevir will remain in force until at least 2025,37 After which time it should be possible to produce generic versions at much lower cost, provided no additional patents are granted for modifications such as route of synthesis, crystalline structures or methods of use. Such ‘evergreen’ patenting has happened repeatedly in HIV drug development and could further delay the introduction of generic DAAs.19,38 In the near future, there need to be negotiations with the patent holders on voluntary licensing, access prices for low and middle income countries, and mass production of low cost DAAs. Unless these DAAs are widely introduced, current death rates from HCV of 500,000 people per year will continue for many years to come.

Finally, our analysis is limited to HCV DAAs that have been mainly evaluated in genotype 1 HCV. Although sofosbuvir has recently been approved in combination with ribavirin for the treatment of genotypes 2 and 3, further research needs to be conducted to ensure pan-genotypic coverage of HCV.

The high cost of drugs is often justified by the need to recover costs of research and development (R&D). In the case of antiretrovirals for HIV, many of these costs were assumed by the public sector, where parts of the drug discovery and development occurred.39 Several mechanisms have been used by originator companies to allow access to antiretrovirals in low-income settings. These include differential pricing (charging more in high-income countries) and voluntary licensing (allowing third party generic manufacture). Similar mechanisms could be employed for HCV DAAs to ensure these drugs are affordable, while also providing a financial return on the costs of research and development.40 Commitments by national governments to scale up antiretroviral therapy, with support from international donors, were also critical to leveraging prices by increasing the size and predictability of the HIV market. This will be an essential factor in lowering drug prices and increasing access to HCV DAAs.41

Expanding access through greater affordability will also confer indirect benefits. Currently a large proportion of untreated patients continue to spread the HCV pandemic worldwide. Lessons learnt from HIV suggests that with the introduction of strong community programmes for testing, and high rates of treatment coverage and retention, expanded access to treatment is also likely to have a pronounced effect on HCV transmission, a benefit already suggested in modelling studies.42

Widespread access to HCV DAAs will also require fast regulatory approvals of new drugs, political will, establishment of national viral hepatitis programs, early access programs to start treating people who are most at risk, and accepted international HCV treatment guidelines.

In conclusion, widespread access to combinations of HCV DAAs is feasible, with potential target prices of US$100-250 per person for a 12 week treatment course. Progressive reductions in these costs are likely through optimisation of chemical synthesis and cheaper sourcing of raw materials. These low prices could make widespread access to HCV treatment in low and middle income countries a realistic goal, with substantial individual and public health benefits.

Source of funding: There was no funding provided for this project. All the authors contributed their time and resources voluntarily.

Conflicts of interest: JF, BS and NF report no conflicts of interest. AH has received consultancy payments from Janssen, not connected with this project. SK has received consultancy payments and travel grants from pharmaceutical companies, not connected with this project.

Authors’ contributions: Andrew Hill wrote the original plan for analysis and coordinated the project. Bryony Simmons conducted the literature search and compiled the data for analysis. Joe Fortunak worked on the routes of chemical synthesis and raw materials. Nathan Ford worked on the patent access issues. Saye Khoo worked on the clinical issues in treatment of Hepatitis C. All authors critically reviewed the manuscript and approved the final version. 

Additional figures see pages 24-28 of PDF

References (See pages 20 – 23 of PDF)

Capture4
* Sofosbuvir is presumably synthesized as a mixture of diastereomers on  phosphorous. Only one f these two diastereomers is desired in the API. Separation  of diastereomers can be a substantial contributor to the cost of API production,  particularly when an undesired diastereomer cannot be fficiently recycled. See US  Patent 7,390,791 and US Application 20130065856 for the tenofovir alafenamide  fumarate (TAF) prodrug version of tenofovir which contains an identical “ProTide™”  oiety as that present in Sofosbuvir. Efficient recycling of diastereomers has been  demonstrated for AF, but we do not presume this is the case for Sofosbuvir.

Source

Liver International

Special Issue: Proceedings of the 7th Paris Hepatitis Conference International Conference of the Management of Patients with Viral Hepatitis, 13–14 January 2014, Paris, France. Guest Editors: Patrick Marcellin and Tarik Asselah. The publication of this supplement was supported by an unrestricted educational grant from Gilead, Janssen Therapeutics, Janssen, Bristol-Myers Squibb, Roche, Boehringer Ingelheim, Merck, AbbVie, Novartis, Idenix and Alios.

Volume 34, Issue Supplement s1, pages 85–90, February 2014

Review Article

You have free access to this content

Vincenza Calvaruso*, Antonio Craxì

Article first published online: 23 DEC 2013

DOI: 10.1111/liv.12395

© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Keywords: antiviral therapy;  chronic hepatitis B;  hepatocellular carcinoma;  liver fibrosis

Abstract

Long-lasting HBV-DNA suppression is considered to be the best surrogate end-point of antiviral therapy in patients with hepatitis B virus (HBV) related chronic hepatitis or cirrhosis, and it is a prerequisite to prevent liver-related complications and improve survival. Treatment with oral antiviral drugs in patients with HBV cirrhosis is effective in restoring liver function and improving survival even in those with decompensated cirrhosis. These agents are generally well-tolerated for long-term treatment, and several evidences have demonstrated that they are able to reverse liver fibrosis and prevent the occurrence of HCC.

In patients with HBV related cirrhosis, antiviral therapy with nucleoside or nucleotide analogues (NAs) should be initiated as soon as the diagnosis has been established. European Association for the Study of the Liver (EASL) Clinical Practice Guidelines [1] suggest that antiviral treatment of HBV cirrhosis is indicated to prevent viral reactivation whatever the serum HBV-DNA levels.

In fact, there is a significant correlation between HBV DNA levels and necroinflammatory activity [2] and since liver fibrosis is mainly stimulated by hepatic necroinflammatory activity [3], the fibrogenetic process could be reduced as a result of the suppression of HBV.

The main goals of antiviral therapy are to prevent liver decompensation, the occurrence of hepatocellular carcinoma (HCC) and to improve survival. However, numerous studies have been performed to assess the progressive changes in liver histology with long-term antiviral therapy. Indeed, even if this is only a surrogate outcome it could help improve the prognosis of HBV related liver damage.

Although advanced liver fibrosis was previously thought to be irreversible, there is evidence to show that cirrhosis can be reversed if the underlying cause of liver injury is eliminated [4-14]. The purpose of this review is to collect the available data from literature focusing the issue of reversibility of liver fibrosis after antiviral therapy in Chronic Hepatitis B.

Natural course of chronic HBV infection

The natural history of chronic HBV infection and disease is complex, thus understanding the clinical outcomes and the factors affecting disease progression is important in the management of this entity [15]. Fattovich et al. [16] performed a systematic review in 2008 assessing the rate of disease progression and the factors influencing the course of liver disease.

The 5-year cumulative incidence of cirrhosis was 8 and 17% in East Asian countries and European countries, respectively, in patients with HBeAg positive chronic hepatitis and 13 and 38%, respectively, in patients with HBeAg negative chronic hepatitis. When they present with compensated cirrhosis at least 30–70% of patients still have active viral replication, which is associated with continued liver disease progression and decreased survival over time [17, 18].

Among host factors, older age is an important determinant of progression to cirrhosis and HCC since it is related to a longer duration of HBV liver disease. Male gender has been also identified as an independent risk factor of cirrhosis [19, 20] and the overall risk of HCC in chronic HBV carriers is three to six times higher in men than in women [21, 22]. The antifibrogenic effect of oestrogen probably explains this association [23].

The incidence of hepatic decompensation and/or oesophageal varices bleeding was 3–4 per 100 person years in patients with early stages of cirrhosis in both European and Asian studies, with a 5-year cumulative incidence of liver decompensation of 15% [5, 24-26].

Decompensation usually presents with at least one episode of ascites, jaundice, hepatic encephalopathy or variceal bleeding [27]. This can develop insidiously or as a complication of an acute hepatitis flare [28]. The latter was demonstrated in a study showing that hepatic decompensation developed in 14% of patients with cirrhosis who experienced hepatitis flares [29]. The prognosis of these two modes of hepatic decompensation have not been clearly differentiated and compared. Other hepatitis virus superinfections in HBV patients with cirrhosis other than active HBV replication could cause decompensation [16, 30].

Once hepatic decompensation occurs, mortality increases significantly, ranging from 70 to 85% at 5-year follow-up in different studies [25, 31]. These patients need to be carefully evaluated. Evaluation of patients with cirrhosis includes liver function status, and the presence of varices. Monitoring of HCC in patients with HBV cirrhosis is mandatory.

The efficacy of antiviral therapy in patients with HBV cirrhosis

Therapy must provide sufficient virological suppression to achieve biochemical remission, histological improvement and the prevention of complications. The ideal outcome is HBsAg loss which unfortunately is infrequent. Moreover, complete eradication of hepatitis B virus (HBV) infection in chronic hepatitis B is not achieved with current therapies. Even in patients who clear HBsAg, HBV remains in infected hepatocytes in the form of covalently closed circular DNA (cccDNA) for the lifetime of the cell, thus, a more realistic goal of therapy is sustained or maintained virological remission [32].

Drugs available for the treatment of CHB include interferon (IFN), PEG-IFN and five NAs. NAs for HBV therapy can be classified into nucleosides (lamivudine, LAM; telbivudine, TBV; entecavir, ETV) and nucleotides (adefovir, ADV; tenofovir, TFV).

Interferon based therapy

Interferon based therapy is not frequently used in patients with cirrhosis. Indeed, even if it has certain advantages such as finite duration, the absence of resistance and higher rates of anti-HBe and anti-HBs seroconversion, there is only a moderate antiviral effect, poor tolerability and a high risk of adverse events [1].

Thus, there is not enough evidence to determine the histological improvement of patients with HBV related cirrhosis following IFN. However, numerous studies have shown how conventional IFN therapy or more recently PEG-IFN can reduce the progression of fibrosis and the occurrence of liver decompensation and HCC both in HBeAg positive and HBeAg negative patients [33-37]. A significant reduction in the incidence of cirrhosis (17.8% vs 33.7% in the controls; P = 0.041) has been demonstrated [33] in a large cohort of HBeAg-positive patients treated with IFN compared with well-matched untreated patients.

Furthermore, an earlier randomized control study showed that IFN therapy reduced the incidence of HCC in patients with HBeAg-positive active chronic hepatitis [34].

Moreover, HBeAg-negative patients who achieved a sustained viral response (SVR) following IFN showed a decrease in the progression of the Ishak fibrosis score or a decreased risk of cirrhosis as well as fewer severe cirrhosis-related complications in the long term, a reduced incidence of HCC, less need for liver transplantation and lower mortality. Unfortunately, a SVR occurred in less than 30% of HBeAg-negative patients [35, 36].

Interferon-based therapy has been shown to be safe in patients with compensated cirrhosis [37] also suggesting that patients with cirrhosis can benefit from IFN based treatment.

A recently published meta-analysis showed a significant reduction in the risk of HCC ranging from a 34% reduction in patients with chronic hepatitis to 47% in patients with cirrhosis [38]. Two other meta-analyses have confirmed that IFN therapy significantly prevented the development of HCC. [10, 39].

Nucleoside and nucleotide analogues

Five different antiviral agents have been approved and treatment with these oral agents has been shown to be life-saving. LAM and ADV and more recently ETV), TBV and TFV have revolutionized the treatment of chronic hepatitis B [40]. These treatments can delay the progression of fibrosis and reverse both fibrosis and cirrhosis [3, 4, 7, 8], Table 1. Furthermore, they prevent hepatic decompensation in patients with advanced fibrosis and cirrhosis [5, 41, 42].

Capture

Lamivudine

LAM was the first oral agent licensed for the treatment of hepatitis B. Clinical trials have shown that LAM therapy can delay the progression of fibrosis, reduce progression to and reverse cirrhosis, prevent liver decompensation in patients with cirrhosis and stabilize patients with hepatic decompensation [4, 5, 43].

In a study from Asia [5], continuous LAM therapy delayed clinical progression in CHB patients and advanced fibrosis or cirrhosis by reducing the incidence of hepatic decompensation and HCC. Similarly, an Italian multicentre study designed to evaluate the clinical outcome of chronic HBV in relation to virological response to LAM [41] found that HBeAg-negative patients with cirrhosis and with a SVR were less likely than those with viral breakthrough to develop HCC and disease progression, and that survival was better in patients with Child A cirrhosis and SVR.

The direct effect of LAM monotherapy on portal pressure in CHB cirrhosis was evaluated in a prospective study by Manolakopoulos et al.[42]. The results of this study show that virological and biochemical response to LAM is associated with a significant decrease in portal pressure in patients with cirrhosis and clinically significant portal hypertension (hepatic venous pressure gradient >10 mmHg).

Although LAM has the most extensive safety record, the high rate of viral breakthrough because of virological resistance to LAM (up to 30% in year 1 and up to 70% at the end of 5 years) and the availability of more potent and effective agents with improved resistance profiles, has reduced its use in patients with chronic hepatitis B especially those with cirrhosis in whom loss of virological response can lead to clinical deterioration.

Adefovir dipivoxil

Although ADV is less potent than LAM, it has mainly been used for LAM-resistant chronic hepatitis B and hepatic decompensation associated with LAM-resistance prior to and after liver transplantation [1, 44]. Indeed, the advantage of this drug was its limited resistance for 1–2 years and the absence of cross-resistance with LAM and other L-nucleosides. Long-term (>3 years) ADV therapy resulted in the improvement of fibrosis or the reversal of advanced fibrosis [6, 9]. Marcellin et al. [9] have shown a significant histological improvement (defined as a reduction of at least 2 points in the Knodell necroinflammatory score with no worsening of the Knodell fibrosis score) in 60% of patients treated with ADV and with liver biopsy before and after antiviral therapy. Hadziyannis et al. [6] observed a significant improvement in liver histology following long-term treatment with ADV.

In this large trial, liver biopsies after 192 (placebo-ADV group) or 240 weeks (ADV group) of treatment showed that necroinflammation improved in 86% and 83% of patients, respectively, and fibrosis improved in 73 and 75%, respectively, compared with pretreatment biopsies.

In a long-term follow-up study of the 226 waiting list patients and 241 post-transplant patients with recurrent hepatitis B because of LAM-resistant HBV, the use of ADV resulted in undetectable HBV DNA in 65% of the waiting list and post-transplant patients after 96 weeks of therapy. Moreover, after 48 weeks of treatment, liver function improved in 50–80% of these patients [44].

Like LAM this drug has been gradually replaced by more recent NAs because of the resistant variants that increase after the first year and reach almost 30% after 4 years [1].

Entecavir

Entecavir (ETV) is a potent inhibitor of viral replication in chronic hepatitis B. In a recent study, an Italian group evaluated the efficacy of ETV in an Italian cohort of unselected patients with different stages of liver fibrosis, comparing the virological and clinical results between patients with and without cirrhosis [45]. This study showed that results with ETV were excellent for patients with HBV liver disease and especially cirrhosis where there was a good tolerability profile, better efficacy and an earlier virological response.

Schiff et al. [11] evaluated the improvement in liver histology in 10 patients with advanced fibrosis or cirrhosis (Ishak fibrosis score 4–6), who received long-term ETV treatment (approximately 6 years, range, 267–297 weeks). All patients had liver biopsies at baseline, week 48, and long term, and histological improvement of at least 1-point on the Ishak fibrosis score was found in all patients after long-term treatment. Similarly, in a study by Chang et al. [12], 96% of patients (55/57) had histological improvement after long-term treatment with ETV. Ten of the 57 patients had advanced fibrosis or cirrhosis (Ishak score 4–6) at the baseline. All 10 patients achieved at least a 1-point reduction in the Ishak fibrosis score after long-term ETV therapy.

Also there was a 6.37-point reduction in the mean Knodell necroinflammatory score after long-term treatment vs a mean reduction of 3.39 points after 48 weeks of ETV therapy.

A more recent study analysing 372 ETV-treated patients including 98 patients with cirrhosis, showed that the virological response to ETV is associated with a lower probability of disease progression (liver decompensation and HCC) in patients with cirrhosis [13].

Finally, Shim et al. [46] prospectively compared the efficacy of ETV in 70 patients with decompensated cirrhosis and 144 patients with compensated CHB. There was no significant difference between the groups in the percentage of patients who achieved undetectable HBV DNA or ALT normalization and HBeAg seroconversion or HBeAg loss after 6 or 12 months of treatment. The Child–Pugh score (CPS) and the Model for End Liver Disease (MELD) score was significantly improved in decompensated patients treated for >12 months and the 2-year cumulative rates of HCC and death or liver transplantation were 6.9 and 17% respectively.

Tenofovir

TFV, the most recently approved drug for hepatitis B, is more potent, more rapid and has a better resistance profile than ADV as well as an excellent safety profile. There are very few data on the outcome of patients with cirrhosis and TFV.

In the study by Marcellin et al. [47], histological improvement was obtained in significantly more patients who received TFV than in those who received ADV (71% vs. 49% in HBeAg-negative patients and 67% vs. 12% in HBeAg- positive patients). Necroinflammation was reduced in most patients. More recently, another study evaluated the histological improvement (≥2 point reduction in Knodell necroinflammatory score with no worsening of fibrosis) and regression of fibrosis (≥1 unit decrease by Ishak scoring system) in a large cohort of patients treated with TFV [14]. At baseline 38% (133/348) of the patients had bridging fibrosis to cirrhosis (Ishak scores of 4 or more), but this rate declined to 28% (97/344) and 12% (42/348) at year 1 and year 5 respectively. Overall, the regression of fibrosis occurred in 51% (176/348) of patients and histological improvement in 304/348 (87%) of patients after 5 years of treatment. Figure 1.

liv12395-fig-0001

Figure 1. Histological response at year 5 according to baseline Ishak fibrosis scores for 348 patients with data available at baseline and year 5 (Marcellin P, Lancet 2013;381: 468–75).

Finally a 2 point reduction in the CPS occurred in 48% of patients with liver decompensation treated with TFV compared with 41.7% treated with ETV, and a median reduction in the MELD score of 2.0 from baseline was reported for both groups [48].

Telbivudine

There are only few data evaluating the real effects of TBV on histological improvement in patients with chronic hepatitis B. In HBeAg-positive patients, TBV seems to be better than LAM in achieving histological improvement (65% vs 56%) but not in obtaining biochemical (77% vs 75%) or serological responses (HBeAg seroconversion in 23% vs 22%). On the contrary, in HBeAg-negative patients, TBV suppressed HBV DNA to undetectable levels in 88% of patients vs 71% of patients treated with LAM but histological improvement (67% vs 66%) and biochemical improvement (74% vs 79%) was not different between the two groups [49].

Conclusion

The goal of treatment for chronic HBV infection is to achieve viral suppression, control liver fibrosis and prevent progression to hepatic decompensation and HCC. Hepatic fibrosis is mainly stimulated by hepatic necroinflammatory activity, and several studies have shown that prolonged antiviral therapy is associated with improvement in liver histology and even reversal of cirrhosis in chronic HBV infection.

However, the evidences available so far, involved a small proportion of patients enrolled in the trials, and consisted of a small number of patients with advanced fibrosis or cirrhosis. Moreover, there is the bias because of selection of patients to undergo repeat biopsy and furthermore the important issue of the correct stain for elastic fibres in liver biopsies. Indeed, mostly in presence of high grade of necroinflammation, there is a parenchymal collapse simulating septa, and in these cases collagen stains (Sirius Red, Masson Thricrome) could lead to a misdiagnosis of cirrhosis which could be evaluated as disappeared in the successive liver biopsies.

In our opinion the amount of liver fibrosis, if correctly evaluated, could be reduced by a switching off of inflammation but we need more and well-designed studies to assess whether the distorted liver parenchyma and altered blood flow in the cirrhotic liver are reversible.

This review has provided an update on these data. All NAs have been shown to improve liver histology in patients with CHC and this is especially true in patients with advanced fibrosis. Improvement in both necroinflammation and the stage of fibrosis prevents decompensation and HCC, significantly changing the prognosis of patients with HBV cirrhosis. For this reason both patients with compensated and decompensated cirrhosis should be promptly and correctly treated with oral antiviral therapy whatever the HBV DNA level as early as possible (Fig. 1).

Available antiviral drugs are safe and effective in improving liver function in this population although only the use of ETV and TFV is highly recommended because of their low risk of resistance.

Disclosure

The authors do not have any disclosures to report.

References

Source

By: WOWT Email
Posted: Thu 8:58 AM, Jan 09, 2014

unmc_logo_320

The University of Nebraska Medical Center in Omaha is involved in an international registry that’s evaluating new treatments for hepatitis C, a disease that threatens many baby boomers.

Many of the estimated three million people in the U.S. who have the virus, an overwhelming majority being baby boomers, don’t know they are infected. Hepatitis C is responsible for 12,000 deaths annually in the U.S, according to the Centers for Disease Control and Prevention.

UNMC, a regional referral center for hepatitis C, is part of the Hepatitis C Therapeutic Registry and Research Network, or HCV-TARGET. The network will track thousands of patients over the next five years to monitor the effectiveness and safety of new drugs to determine which ones are most effective and can cure the disease most quickly with the fewest side effects.

The project is important because in the next few years, several new, more superior medications will be approved for hepatitis C therapy, said Dr. Mark Mailliard, chief of the UNMC Division of Gastroenterology and Hepatology.

“With the availability of new drugs, we will be able to capture a wealth of information that’s critical to determining which drugs are best and for which patients,” said Dr. Mailliard. “This is a great example of translational research at its best, taking the latest research discoveries to patients.”

The network, which receives support from pharmaceutical companies, is made up of university and community physicians at 103 sites in 31 states, Puerto Rico, Canada and Europe, in partnership with the U.S. Food and Drug Administration.

It’s estimated that about two percent of the world’s population is infected with hepatitis C. If left untreated, the virus causes liver damage, cancer or cirrhosis. Fatigue may be the only symptom of the disease.

Anyone being treated for the virus using newer medications is eligible to participate in the registry. Dr. Mailliard said most of the current drugs used to treat hepatitis C, typically interferon and ribavirin, have many side effects and require self-administered injections. But he said over the next three years, the use of interferon will slowly go away because of new drugs that will be more effective with much less side effects.

“We’re really very excited about the registry. So far we’ve provided outcome data on more than 120 patients of the 2,000 studied so far." Our treatment success rate was significantly better than the average rate.”

People born between 1945 and 1965 are encouraged to get tested since many don’t recognize they are at risk for the disease. A simple blood test can diagnose the disease.

“Not only will treatment reduce the chance for liver failure and liver cancer, the diagnosis reminds patients of the danger of alcohol use and obesity, which increase the risk of getting cirrhosis and cancer,” said Dr. Mailliard.

The hepatitis C virus is usually is spread through contact with an infected person’s blood, mostly by sharing needles, syringes or other equipment to inject drugs. Before 1992, when widespread screening of the blood supply began in the U.S., hepatitis C also was commonly spread through blood transfusions.

Source

PUBLIC RELEASE DATE:  9-Jan-2014
Contact: Dawn Peters
sciencenewsroom@wiley.com
781-388-8408
Wiley

Findings published in the American Association for the Study of Liver Diseases journal, Hepatology, indicate that infection, the commonest cause of mortality in patients with acute liver failure (ALF), may be decreased by inhibiting the activity of a protein found in saliva called SLPI (secretory leukocyte protease inhibitor). New research has found that this protein, produced by the body in response to injury, plays a vital role in patients with ALF.

Acute liver failure occurs when there is rapid death of liver cells (hepatocytes). According to the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) drug-induced liver injury, particularly acetaminophen (Tylenol®) overdose, is the most common cause of acute liver failure in the U.S. and other developed countries. Previous studies have demonstrated that infection is the commonest complication in liver failure and is the leading cause of premature death in over 50% patients.

"Infection, namely sepsis, in patients with acute liver failure may be linked to an inadequate response of the body's immune system," explains Dr. C.G. Antoniades, an MRC Clinician Scientist from Imperial College London and King's College London. "Our study is the first to investigate the role of this particular protein in liver failure patients."

A team of scientists and clinicians at King's College London, King's College Hospital NHS Foundation Trust and Imperial College London studied 98 patients with liver failure as well as 24 healthy volunteers. Results show that patients with ALF had elevated levels of this key molecule (SLPI) in the liver and circulating round the body, that impaired the ability of immune cells, monocytes/macrophages, to combat infection. When researchers blocked the activity of the SLPI molecule the function of monocytes/macrophages was restored, similar that seen in healthy individuals. When SLPI protein was added to healthy immune cells, it rendered them poorly responsive to infectious organisms that are commonly encountered in patients with liver failure.

"Our findings indicate that SLPI is a critical mediator of excessive anti-inflammatory responses in ALF which explains the susceptibility to sepsis/infection in these patients," concludes Dr. Antoniades. "Further study of therapeutic options to inhibit the activity of SLPI in the management of sepsis in liver failure are needed."

###

This study is published in Hepatology. Media wishing to receive a PDF of the article may contact sciencenewsroom@wiley.com.

Full citation: "Secretory Leukocyte Protease Inhibitor: A Pivotal Mediator of Anti-Inflammatory Responses in Acetaminophen Induced Acute Liver Failure." Charalambos Gustav Antoniades, Wafa Khamri, Robin D Abeles, Leonie S Taams, Evangelos Triantafyllou, Lucia A Possamai, Christine Bernsmeier, Ragai R Mitry, Alistair O'Brien, Derek Gilroy, Robert Goldin, Michael Heneghan, Nigel Heaton, Wayel Jassem, William Bernal, Diego Vergani, Yun Ma, Alberto Quaglia, Julia Wendon and Mark Thursz. Hepatology; (DOI: 10.1002/hep.26933).

URL: http://doi.wiley.com/10.1002/hep.26933

Author Contact: Media wishing to speak with Dr. Antoniades may contact Sam Wong with Imperial College at sam.wong@imperial.ac.uk or Emma Reynolds with Kings College emma.reynolds@kcl.ac.uk.

About the Journal

Hepatology is the premier publication in the field of liver disease, publishing original, peer-reviewed articles concerning all aspects of liver structure, function and disease. Each month, the distinguished Editorial Board monitors and selects only the best articles on subjects such as immunology, chronic hepatitis, viral hepatitis, cirrhosis, genetic and metabolic liver diseases and their complications, liver cancer, and drug metabolism. Hepatology is published on is published by Wiley on behalf of the American Association for the Study of Liver Diseases (AASLD). For more information, please visit http://wileyonlinelibrary.com/journal/hep.

About Wiley

Wiley is a global provider of content-enabled solutions that improve outcomes in research, education, and professional practice. Our core businesses produce scientific, technical, medical, and scholarly journals, reference works, books, database services, and advertising; professional books, subscription products, certification and training services and online applications; and education content and services including integrated online teaching and learning resources for undergraduate and graduate students and lifelong learners.

Founded in 1807, John Wiley & Sons, Inc. (NYSE: JWa, JWb), has been a valued source of information and understanding for more than 200 years, helping people around the world meet their needs and fulfill their aspirations. Wiley and its acquired companies have published the works of more than 450 Nobel laureates in all categories: Literature, Economics, Physiology or Medicine, Physics, Chemistry, and Peace. Wiley's global headquarters are located in Hoboken, New Jersey, with operations in the U.S., Europe, Asia, Canada, and Australia. The Company's website can be accessed at http://www.wiley.com.

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Intercept liver drug meets main goal in study, shares quadruple

BY VRINDA MANOCHA
Thu Jan 9, 2014 9:43am EST

(Reuters) - Intercept Pharmaceuticals Inc's drug to treat liver disease caused by fat buildup was found effective in a trial, paving the way for it to become the first approved treatment for the chronic condition.

The company's shares nearly quadrupled to a life high of $305 on Thursday morning on theNasdaq, valuing the company at about $6 billion.

Intercept said it had stopped the trial after the drug showed statistically significant improvement in patients, compared with a placebo, in a review by an independent safety committee.

The trial tested the drug, obeticholic acid, in patients with non-alcoholic steatohepatitis (NASH), a form of liver inflammation.

Analysts said the news came as a surprise to investors, who had previously focused on the drug as a treatment for primary biliary cirrhosis, an autoimmune disease in which bile ducts in the liver are destroyed. The drug is being tested for the condition in a late-stage study.

"We didn't expect this data until the fourth quarter," Wedbush analyst Liana Moussatos said. "It's a huge opportunity for the company as there are over 10 million patients worldwide."

Moussatos said Intercept could tie up with Big Pharma companies to conduct a late-stage trial of the drug. Intercept could also conduct a late-stage trial with its partner Dainippon Sumitomo Pharma, which is testing the drug in Japan, she said.

Obeticholic acid, Intercept's lead drug, is also being tested in mid-stage studies to treat bile acid diarrhea and portal hypertension, which is high blood pressure in veins that transport blood from the gastrointestinal tract and spleen to the liver.

The drug's structure is similar to that of a naturally occurring human bile acid.

Intercept said the safety committee made the recommendation after reviewing liver biopsy data from about half of the 283 patients enrolled in the mid-stage trial.

There is currently no specific treatment for NASH, according to the U.S. National Institutes of Health.

To manage the disease, patients are recommended to maintain a healthy weight, follow a balanced diet, increase physical activity and avoid alcohol.

(Reporting by Vrinda Manocha in Bangalore; Editing by Kirti Pandey)

Source

January 9, 2014

RenderImage

BOSTON--(BUSINESS WIRE)-- Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today announced the first data from the initial cohorts of an open-label Phase 2a study of VX-135, Vertex's nucleotide analogue hepatitis C virus (HCV) polymerase inhibitor, in combination with daclatasvir, Bristol-Myers Squibb's NS5A replication complex inhibitor. In an intent-to-treat analysis, the sustained viral response rate four weeks after the completion of treatment (SVR4) was 83 percent (10 of 12) in treatment-naïve genotype 1 patients who received 200 mg of VX-135 in combination with daclatasvir. In this arm, one patient discontinued treatment after the first dose due to a serious adverse event of vomiting/nausea. The 11 other patients in this arm completed 12 weeks of treatment, and 91 percent (10 of 11) achieved SVR4. In the study, the majority of adverse events were mild.

"We are encouraged by these initial Phase 2a data for VX-135 in combination with another direct acting antiviral medicine," said Robert Kauffman, M.D., Ph.D., Senior Vice President and Chief Medical Officer at Vertex. "We believe that VX-135 has the potential to play an important future role in the treatment of hepatitis C, and we are currently evaluating these data with BMS to determine the next steps for this combination in people with hepatitis C, including people with genotypes 1 and 3."

About the Phase 2a Study

The data announced today are from the first two cohorts of an open-label Phase 2a study of VX-135 in combination with daclatasvir. The initial two cohorts of the study evaluated 100 mg and 200 mg once-daily doses of VX-135 in combination with daclatasvir once daily (60 mg) for 12 weeks of total treatment. Twenty-three people with chronic genotype 1 hepatitis C who were new to treatment (treatment-naïve) and did not have liver cirrhosis were enrolled in these cohorts. More than 75 percent of all patients enrolled had genotype 1a HCV. The majority of adverse events observed in the study were mild. The most common adverse events observed in greater than 10 percent of patients across the study were fatigue, headache and nausea. Safety and efficacy data for the two arms of the study are provided below:

  • 200 mg of VX-135 in Combination with Daclatasvir (60 mg): In an intent-to-treat analysis, 58 percent (7 of 12) of patients had undetectable HCV RNA after 4 weeks of treatment and 83 percent (10 of 12) of patients had undetectable HCV RNA four weeks after the completion of treatment (SVR4). One patient in this arm experienced a serious adverse event of vomiting/nausea, discontinued treatment after the first dose and did not acheive SVR4. The 11 other patients in this arm completed 12 weeks of treatment, and 91 percent (10 of 11) achieved SVR4. One patient relapsed during the follow-up period and did not achieve SVR4.
  • 100 mg of VX-135 in Combination with Daclatasvir (60 mg): In an intent-to-treat analysis, 73 percent (8 of 11) of patients achieved undetectable HCV RNA after 4 weeks of treatment and 73 percent (8 of 11) of patients had undetectable HCV RNA four weeks after the completion of treatment (SVR4). Two patients in this arm experienced viral breakthrough while receiving the combination regimen, and one patient relapsed during the follow-up period.

Vertex expects to submit these data for presentation at a medical meeting in 2014.

About VX-135

VX-135 is a uridine nucleotide analogue pro-drug designed to inhibit the replication of the hepatitis C virus by acting on the NS5B polymerase. Vertex gained worldwide rights to ALS-2200, known as VX-135 in Phase 2 studies, through an exclusive licensing agreement signed with Alios BioPharma, Inc. in June 2011.

About Vertex

Vertex is a global biotechnology company that aims to discover, develop and commercialize innovative medicines so people with serious diseases can lead better lives. Vertex scientists and our collaborators are working on new medicines to cure or significantly advance the treatment of cystic fibrosis, hepatitis C, rheumatoid arthritis and other life-threatening diseases. In addition to our clinical development programs, Vertex has more than a dozen ongoing preclinical programs aimed at other serious and life-threatening diseases.

Founded in 1989 in Cambridge, Mass., Vertex today has research and development sites and commercial offices in the United States, Europe, Canadaand Australia. For four years in a row, Science magazine has named Vertex one of its Top Employers in the life sciences. For additional information and the latest updates from the company, please visit www.vrtx.com.

Vertex Special Note Regarding Forward-Looking Statements

This press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, including, without limitation, Dr. Kauffman's statements in the second paragraph of the press release. While Vertex believes the forward-looking statements contained in this press release are accurate, there are a number of factors that could cause actual events or results to differ materially from those indicated by such forward-looking statements. Those risks and uncertainties include, among other things, that there is a partial clinical hold on VX-135 in the United States, that the outcomes of Vertex's clinical studies of VX-135 may not be favorable or support further development of VX-135 due to safety, efficacy, or other reasons, and the other risks listed under Risk Factors in Vertex's annual report and quarterly reports filed with the Securities and Exchange Commission and available through the company's website at www.vrtx.com. Vertex disclaims any obligation to update the information contained in this press release as new information becomes available.

(VRTX — GEN)

Vertex Pharmaceuticals Incorporated
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Source: Vertex Pharmaceuticals Incorporated

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