Disclosing Hep C Status in the Workplace

May 15, 2013

Deciding whether or not to tell your boss you have Hepatitis C is a multifaceted issue that requires education, planning and support.

Sharing your Hepatitis C status with employers or coworkers can be riddled with complexity. Whether interviewing for a new job, changing health insurance plans, being recently diagnosed or about to begin antiviral therapy, there are many factors to consider before disclosing that you have chronic Hepatitis C. There are no hard and fast rules for how to handle this topic, especially since each individual’s health and employment situation are unique. Knowing where the law lies and reviewing some of the issues involved are helpful when navigating the challenge of Hepatitis C disclosure at work.

Drug Stigma

The stigma associated with Hepatitis C infection represents the biggest barrier to disclosing having this viral illness. More specifically, the hardest stigma to confront relates to the assumption that this infection is due to injection drug use. This could – or could not – be the source of your infection, as there are countless ways Hepatitis C is spread. Regardless of how you acquired Hepatitis C, our society lacks compassion and understanding about injection drug use:

• Those who never used injection drugs do not want to be associated with it.
• Former injection drug users may feel haunted by their past and want to forget it.
• Active injection drug users carry the burden of having two stigmatized diseases – addiction and Hepatitis C.

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'HCV Test & Treat': Routine HCV Screening for All, Rapid HCV Test in Clinic. Baby Boomers, High Risk Populations

Provided by NATAP

from Jules of NATAP: below are 2 letters published in the May 7 2013 issue of Annals of Internal Medicine addressing the CDC recommendation to screen 'baby boomers', those born during 1945-1965, and a letter in response from the CDC's John Ward & Bryce Smith. My response as I have always maintained is we should screen everyone in the USA for HCV, "HCV Test & Treat" like in HIV, but the difference is HCV is curable & will be with 12 weeks therapy without interferon; it could be implemented by including HCV testing in the regular panel of bloodwork one receives upon visiting a clinician's office OR & I prefer this method, we should regularly use HCV rapid testing in the healthcare provider's office at the clinic upon a visit, this would prevent a person not knowing they have HCV because they never returned to get results or address poor communication between patient & healthcare provider, AND if the antibody test were positive or the rapid test positive this SHOULD automatically provide a signal that followup HCV panel should be performed including HCV-RNA. Considering that we soon will have new HCV therapies that are IFN-free, 12 weeks in duration and will be able to 'cure' most people, this is a very unique time in medical history requiring a unique novel response. For the first time in medical history we will be able to cure a virus, a viral infection, with limited duration of therapy, with a relatively innocuous therapy & for a relatively very brief duration of therapy. We need to institute a system that is responsive to this unique time in medical history & to take advantage of this opportunity. To do so is cost effective & saves lives, the cost of not doing this is a tremendous cost & burden to the healthcare system, with as HCV+ patients age & progress in disease over the next 10 years the cost associated with advancing liver disease is in the billions of dollars in care, for those with cirrhosis, decompensated cirrhosis, liver cancer (HCC), and end stage liver disease. The burden of these costs will accrue to all levels of government, particularly cities & states, to private insurers, to Medicaid & to Medicare. It is less costly to implement a system that may seem in the beginning to be a bit more costly & cumbersome but in the end will save money & lives. So, in sum we should TEST EVERYONE in the USA for HCV & use the rapid HCV test. We could design a system that uses both, including HCV screening in the panel of bloodwork every person receives when visiting their clinic & also use the rapid HCV test, we could very easily design a system that utilizes both.

Hepatitis C Virus Testing of Persons Born During 1945-1965
Richard B. Lynn, MD
[+] Article and Author Information

TO THE EDITOR:
Recommendations by the Centers for Disease Control and Prevention (CDC) (1) have expanded screening for hepatitis C virus (HCV) from those at increased risk for infection to the entire age cohort born during 1945-1965. This recommendation was based on the relatively high risk for infection in this group. Consideration was given to benefit versus risk for the individual patient as well as a cost analysis for screening the age cohort population (2). However, the cost analysis should have been performed for a different population: the group that was added to the screening recommendations-those in the age cohort who are not at increased risk for infection.

This age cohort has a relatively high incidence of HCV, but a large portion of the infected persons is derived from the relatively small group of those who are at high risk. Although numerous risk factors are listed, an earlier study (3) reported that one half of the risk for HCV infection for persons between the ages of 20 and 59 years comes from the 1.1% who had ever injected illicit drugs. Adding the 3.4% who received a transfusion before 1992 and the 6.1% with 20 or more lifetime sexual partners accounts for three quarters of the risk for HCV infection. If persons with an elevated alanine aminotransferase level are also tested, 93.5% of the HCV-infected population would be identified.

In justifying the new guidelines, the CDC states that the accuracy of patient recall of risk behaviors decreases over time, but this assumption is based on a meta-analysis about HIV-infected patients that compared 1-, 3-, and 6-month recall (4). Of interest, for "heroin use" and "number of sex partners," 6-month recall was the best. This assumption of poor recall for healthy patients being considered for HCV screening is not adequately evidence-based. I, for one, born in 1956, am confident that I would remember if I had ever injected drugs, received a blood transfusion, or had 20 or more sexual partners.

If the high-risk group is excluded from the age cohort, the result is a large population with a low risk for infection. I suspect that a cost analysis of screening for HCV of this low-risk population would find it not to be cost-effective. In addition, the benefit versus risk of screening this low-risk population would need to be considered.

The key point is that the CDC has added this large population-those born during 1945-1965 who are not at increased risk-to their recommendations for HCV screening. This recommendation would result in the screening of millions of additional persons and cost billions of dollars. Before this step is taken, cost-effectiveness studies and benefit-versus-risk analyses should be done for this low-risk population. At this point, what screening should be recommended to an individual patient who reliably claims not to be at increased risk for HCV is unclear.

References

1 Smith BD, Morgan RL, Beckett GA, Falck-Ytter Y, Holtzman D, Ward JW. Hepatitis C virus testing of persons born during 1945-1965: recommendations from the Centers for Disease Control and Prevention. Ann Intern Med. 2012;157:817-22. PubMed

2 Rein DB, Smith BD, Wittenborn JS, Lesesne SB, Wagner LD, Roblin DW, et al. The cost-effectiveness of birth-cohort screening for hepatitis C antibody in U.S. primary care settings. Ann Intern Med. 2012;156:263-70. PubMed CrossRef

3 Armstrong GL, Wasley A, Simard EP, McQuillan GM, Kuhnert WL, Alter MJ. The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med. 2006;144:705-14. PubMed CrossRef

4 Napper LE, Fisher DG, Reynolds GL, Johnson ME, et al. HIV risk behavior self-report reliability at different recall periods. AIDS Behav. 2010;14:152-61. PubMed CrossRef

------------------------------

Letters | 7 May 2013
Hepatitis C Virus Testing of Persons Born During 1945-1965

Ephraim Back, MD, MPH
[+] Article and Author Information

TO THE EDITOR:
The HCV screening guideline released by the CDC promotes universal screening of all persons born during 1945-1965 (1 - 2). Although this strategy will identify many previously undiagnosed persons who are chronically infected with HCV, it will also lead to many persons being falsely diagnosed with past HCV infection.

Per a 2003 CDC guideline on HCV testing, the proportion of false-positive HCV antibody test results among immunocompetent populations with anti-HCV prevalence less than 10% averages approximately 35% (range, 15% to 60%). This testing guideline warns that "not relying exclusively on anti-HCV screening-test-positive results to determine whether a person has been infected with HCV is critical" and recommends that all positive screening results be verified with a "supplemental test with high specificity" (3).

The HCV nucleic acid test, which is currently recommended for confirmation, can distinguish between active and past infection but not between true- and false-positive results. The HCV recombinant immunoblot assay (RIBA), which can verify true infection, is unfortunately unavailable in the United States. Although the CDC guideline acknowledges that certain harms ("worry or anxiety while waiting for test results, insurability") can result from universal screening, it does not address the very real harm of false diagnosis (with implications about past or present risk behaviors), which can occur in one third of persons who test positive.

Furthermore, the current guideline published in the Morbidity and Mortality Weekly Report: Recommendations and Reports does not even consider the possibility of false-positive results, stating that "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 (i.e., cleared)" (2). At the very least, before adopting universal screening by using a highly sensitive HCV antibody test with no highly specific confirmatory test, physicians need to receive accurate information about the interpretation of HCV antibody tests to be able to appropriately counsel patients who test positive for these antibodies.

References

1Smith BD, Morgan RL, Beckett GA, Falck-Ytter Y, Holtzman D, Ward JW, et al. Hepatitis C virus testing of persons born during 1945-1965: recommendations from the Centers for Disease Control and Prevention. Ann Intern Med. 2012;157:817-22. PubMed

2Smith BD, Morgan RL, Beckett GA, Falck-Ytter Y, Holtzman D, Teo CG, et al. Centers for Disease Control and Prevention. Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945-1965. MMWR Recomm Rep. 2012;61: ((RR-4)) 1-32. PubMed

3Alter MJ, Kuhnert WL, Finelli L, Centers for Disease Control and Prevention. Guidelines for laboratory testing and result reporting of antibody to hepatitis C virus. Centers for Disease Control and Prevention. MMWR Recomm Rep. 2013;52: ((RR-3)) 1-13. PubMed

----------------------

Hepatitis C Virus Testing of Persons Born During 1945-1965

Bryce D. Smith, PhD; Deborah Holtzman, PhD; and John W. Ward, MD [+] Article and Author Information

See Also:
· Hepatitis C Virus Testing of Persons Born During 1945-1965:
Recommendations From the Centers for Disease Control and Prevention

This letter concerns the article(s):
· Hepatitis C Virus Testing of Persons Born During 1945-1965
· Hepatitis C Virus Testing of Persons Born During 1945-1965

IN RESPONSE:
We agree with Dr. Lynn's assertion that effective screening for a history of injection drug use, receipt of blood products before 1992, and testing for elevated alanine aminotransferase levels would identify most chronic HCV infections among persons born during 1945-1965. The CDC has recommended risk-based screening since 1998 (1). Unfortunately, risk-based screening alone has had limited success, because 45% to 85% of infected persons are unaware of their infection (2). Not only are persons unaware of having had a risk that led to infection, studies have also shown that physicians often do not ask their patients about high-risk behaviors, especially behaviors considered sensitive. Furthermore, even when alanine aminotransferase levels are persistently elevated, only a minority of patients are tested for HCV (3 - 4).

Consequently, risk-based testing alone is insufficient to reduce HCV-associated morbidity and mortality, which is increasing in the United States. Augmenting risk-based testing with testing of the 1945-1965 birth cohort, a population accounting for 76% of persons who have been infected with HCV, is thus a reasonable strategy to overcome the problems of patient disclosure and physician reluctance to solicit risk information (5).

Dr. Lynn also asserts that the cost-effectiveness analysis should have been based on a birth-cohort population that excluded persons at high risk for infection. Because birth-cohort testing applies to persons at all levels of risk born during those years, excluding persons at high risk from the cost-effectiveness analysis model would be inappropriate. The model that the CDC developed is most sensitive to the high costs of treatment. In our sensitivity analysis, the costs of testing account for only about 10% of the total cost of the intervention and therefore have a relatively small effect on its cost-effectiveness (6).

Although this is less cost-effective at lower prevalence levels, the difference that would result from removing those that had already been tested would not be sufficient to change the conclusion that the overall intervention is cost-effective. Another challenge is the lack of data on the proportion of high-risk persons who have not yet been tested, limiting our ability to estimate the number of persons who would be tested.

Dr. Back expresses concern that implementing the recommendation would result in many persons receiving false-positive diagnoses of HCV infection. However, 2003 guidelines for laboratory testing and result reporting of HCV antibodies recommended following a weak reactive HCV antibody test with RIBA to confirm antibody status, thus minimizing false-positive results for antibodies (7).

Because RIBAs are no longer available, the CDC recommends an HCV RNA test, thus focusing on identification of HCV viremia rather than antibody positivity. In this way, the presence of current HCV infection can be determined.

Testing to detect current HCV infection is a 2-step process. First, HCV antibody tests identify persons exposed to HCV (but do not determine active infection status). Then, HCV RNA testing (using nucleic acid tests) determines whether someone is currently infected. Therefore, an anti-HCV-positive result that is HCV RNA-negative cannot be a false-positive diagnosis of infection, because the interpretation of those results is that the patient is not infected.

The CDC's birth cohort recommendation shifts the focus away from HCV antibodies to identification of infection, because this provides clinically actionable data. Identification of current infection is the first step toward prevention services that can reduce the risk for transmission to others, slow fibrosis progression, and evaluate clinical markers to make decisions about providing treatment to reduce HCV-related morbidity and mortality.

References

1Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. Centers for Disease Control and Prevention. MMWR Recomm Rep. 1998;47: ((RR-19)) 1-39. PubMed

2Smith BD, Morgan RL, Beckett GA, Falck-Ytter Y, Holtzman D, Teo CG, et al. Centers for Disease Control and Prevention. Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945-1965. MMWR Recomm Rep. 2012;61: ((RR-4)) 1-32. PubMed

3Spradling PR, Rupp L, Moorman AC, Lu M, Teshale EH, Gordon SC, et al. Chronic Hepatitis Cohort Study Investigators. Hepatitis B and C virus infection among 1.2 million persons with access to care: factors associated with testing and infection prevalence. Clin Infect Dis. 2012;55:1047-55. PubMed CrossRef

4Rein DB, Wagner D, Brown K, Fallon M, Federman A, Massoud, et al. Hepatitis C antibody testing and follow-up in primary care settings: a retrospective study of four large, primary care service centers infection among persons born during 1945-1965 in the United States. Presented at the 2012 National Summit on HIV and Viral Hepatitis Diagnosis, Prevention and Access to Care, Washington, DC, 26-28 November 2012.

5Smith BD, Patel N, Beckett G, Ward JW. Comparison of hepatitis C virus infection screening strategies: elevated alanine aminotransferase levels versus birth cohort. Presented at the 2011 American Association for the Study of Liver Disease Liver Meeting, San Francisco, California, 4-6 November 2011.

6Rein DB, Smith BD, Wittenborn JS, Lesesne SB, Wagner LD, Roblin DW, et al. The cost-effectiveness of birth-cohort screening for hepatitis C antibody in U.S. primary care settings. Ann Intern Med. 2012;156:263-70. PubMed CrossRef

7Alter MJ, Kuhnert WL, Finelli L, et al. Centers for Disease Control and Prevention. Guidelines for laboratory testing and result reporting of antibody to hepatitis C virus. Centers for Disease Control and Prevention. MMWR Recomm Rep. 2003;52: ((RR-3)) 1-13. PubMed

Source

The Burgeoning HIV/HCV Syndemic in the Urban Northeast: HCV, HIV, and HIV/HCV Coinfection in an Urban Setting

PLoS One

PLoS One (2013; doi:10.1371/journal.pone.0064321).

Research Article

Jamie P. Morano mail, Britton A. Gibson, Frederick L. Altice

Abstract

Introduction

Despite recommendations for generation-based HCV and once lifetime HIV screening, thousands of individuals in the U.S. still remain untested and undiagnosed. This cross-sectional study examines the correlates of HCV and HIV monoinfection and HIV/HCV coinfection in an urban Northeast setting.

Methods

Utilizing an electronic database from a mobile medical clinic in New Haven, CT from January 2003 to July 2011, 8,311 individuals underwent structured health assessment and screening for HIV and HCV.

Results

HIV [N = 601 (8.0%)] and HCV [N = 753 (10.1%)] infection were identified, and 197 (26.1%) of the 753 with HCV were coinfected with HIV. Both monoinfection and coinfection status were independently correlated with crack cocaine use and increasing age. HIV/HCV coinfection was correlated with men having sex with men (MSM) (AOR = 38.53, p<0.0080), shooting gallery use (AOR = 3.06, p<0.0070), and not completing high school (AOR = 2.51, p<0.0370). HCV monoinfection correlated with health insurance (AOR = 2.16, p<0.0020), domestic violence (AOR = 1.99, p<0.0070), and being Hispanic (AOR = 2.63, p<0.0001), while HIV monoinfection correlated with having had syphilis (AOR = 2.66, p<0.0001) and being Black (AOR = 1.73, p = 0.0010).

Conclusions

Though HIV and HCV share common transmission risk behaviors, independent correlates with viral infection status in an urban Northeast setting are distinct and have important implications for surveillance, healthcare delivery, disease prevention, and clinical care.

Citation: Morano JP, Gibson BA, Altice FL (2013) The Burgeoning HIV/HCV Syndemic in the Urban Northeast: HCV, HIV, and HIV/HCV Coinfection in an Urban Setting. PLoS ONE 8(5): e64321. doi:10.1371/journal.pone.0064321

Editor: Joan A. Caylà, Public Health Agency of Barcelona, Spain

Received: December 11, 2012; Accepted: April 14, 2013; Published: May 14, 2013

Copyright: © 2013 Morano et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: Funding for the study was provided by the National Institutes on Drug Abuse for Career Development (FLA: K24 DA017072) and Research (FLA: R01 DA030762, R01 DA029910) and The National Institutes of Allergy and Infectious Diseases (JPM: T32 A1007517). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: JPM, BAG, and FLA have declared that no competing interests exist. The authors adhere to all PLOS ONE policies on sharing data and materials.

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Risk for liver-related death far greater in HCV seropositive patients with HIV

Provided by Healio

Rockstroh JK. J Hepatol. 2013;doi:10.1016/j.jhep.2013.04.005.

May 15, 2013

Patients who were hepatitis C virus seropositive and coinfected with HIV had nearly a ninefold increased risk for liver-related death compared with patients who were HCV seronegative with no correlations to HCV viremia level or genotype in a recent study.

In a prospective study, researchers enrolled 13,025 patients (mean age, 37.5 years; 74.2% men) with HIV and known HCV antibody (HCVAb) from the EuroSIDA cohort (1994-2011) that included 18,295 HIV-1 infected patients from 105 centers in Europe, Israel and Argentina. Thirty-one percent of the patients had detectable HCVAb (n=4,044), including 3,745 who were seropositive at baseline and the remainder who initially were HCVAb negative but showed detectable anti-HCV antibodies during follow-up.

After adjustment, HCVAb positive patients had a statistically significant incidence rate ratio (IRR) of 8.9 (95% CI, 5.6-14.14) for liver-rated death (LRD) compared with HCVAb negative patients. Multivariables included sex, race, previous AIDs, region of Europe, age, HCV treatment status at baseline and exposure group.

Among 1,907 patients with evaluable HCV RNA, 52.9% were infected with HCV genotype 1; 3.3%, 29.7% and 14.2% had genotypes 2, 3 and 4, respectively. Patients with detectable HCV RNA had a greater but not significantly increased incidence of non-LRD (adjusted IRR=1.18; 95% CI, 0.93-1.5) compared with HCVAb positive patients without viremia, while their incidence of LRD was significantly increased (adjusted IRR=2.11; 95% CI, 1.30-3.42).

Researchers said HCV genotype and HCV RNA levels did not affect the risk for LRD or non-LRD among patients with HCV viremia.

“Our results demonstrate that patients with chronic HCV infection had an increased risk of liver-related death compared to patients with undetectable HCV RNA,” the researchers concluded. “However, levels of HCV viremia as well as the presence of HCV genotype 1 do not independently impact clinical outcome and survival in HIV/HCV coinfected patients.

“The ninefold increase of liver-related deaths in HCVAb positive compared to HCVAb negative patients once again underlines the urgent need to develop improved HCV treatment options in this particular patient group.”

Source

Hepatitis C virus is a major challenge for this region, WCMC-Q expert says

Provided by Zawya

Doha - May 15, 2013

About 150 million people are chronically infected and at risk of developing liver cirrhosis and/or liver cancer, and more than 350 000 people die from Hepatitis C Virus (HCV) related liver diseases every year, Dr. Laith Abu-Raddad said last night at a community health forum in Doha.

Dr. Abu-Raddad was addressing the monthly Medicine & U health outreach program at Weill Cornell Medical College in Qatar -Q in Education City.

"HCV currently affects about two per cent of the world's population, we will focus our attention on Egypt tonight, which has the highest HCV prevalence in the world with about 15 per cent of its population infected with the virus," Dr. Abu Raddad said.

Hepatitis C virus is a major cause of liver disease and liver cancer. It is usually spread through the sharing of infected needles, receiving infected blood and other exposures to blood or bodily fluids. The World Health Organization (WHO) estimates that every year, 3-4 million people are newly infected with HCV.

"The current situation in Egypt was ironically started as a consequence of health care campaigns conducted from the 1950s to the early 1980s against schistosomiasis (known commonly as bilharzia). Addressing Hepatitis C is one of the largest health challenges faced by this country today, and has strained its resources by dealing with a large pool of about six million chronically infected people." Dr. Abu-Raddad said.

In his presentation, Dr. Abu-Raddad described how the HCV epidemic has emerged including the contextual factors surrounding its emergence. Causes of current new infections and the latest advances in scientific research on this epidemic were highlighted and the talk included a discussion of the key priorities in relation to prevention programs and scientific research.

Dr. Abu-Raddad is Associate Professor of Public Health, Principal Investigator of the Infectious Disease Epidemiology Group, and the Director of the Biostatistics, Epidemiology and Biomathematics Research Core at WCMC-Q's.

-Ends-

About Weill Cornell Medical College in Qatar
Weill Cornell Medical College in Qatar is a partnership between Cornell University and Qatar Foundation. It offers pre-medical and medical courses leading to the Cornell University MD degree with teaching by Cornell and Weill Cornell faculty and by physicians at Hamad Medical Corporation and Aspetar Orthopedic and Sports Medicine Hospital who hold Weill Cornell appointments. Through its biomedical research program, WCMC-Q is building a sustainable research community in Qatar while advancing basic science and clinical research. Through its medical college, WCMC-Q seeks to provide the finest education possible for medical students, to improve health care both now and for future generations, and to provide highest quality of health care to the Qatari population.

www.qatar-med.cornell.edu

For more info, please contact:
Hanan Lakkis
Media Relations Manager
Weill Cornell Medical College in Qatar
Mobile: +974 55536564
Direct Line: +974 4492866
hyl2004@qatar-med.cornell.edu

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Drug 'may reverse liver disease'

Cirrhosis is a major killer in the UK

Last Updated: Tuesday, 26 September 2006, 15:08 GMT 16:08 UK

A cheap and readily available drug could reverse severe liver disease, even in patients who find it impossible to give up booze, research suggests.

Sulfasalazine is currently used to treat arthritis and inflammatory bowel disease.

But a University of Newcastle team has found that it can also reverse the scarring associated with cirrhosis of the liver.

Liver disease is the fifth highest cause of death in the UK.

It is estimated that up to 10% of the UK population have problems with their liver - and most are linked to lifestyle factors, such as heavy drinking and obesity.

Scientists had thought that the scarring associated with cirrhosis - known as fibrosis - was irreversible.

However, recent studies have shown that is not the case.

Now the Newcastle team, in tests on animals, have shown that sulfasalazine can aid the recovery process.

Regeneration

When the liver is injured specialised cells called hepatic myofibroblasts create scar tissue, and secrete proteins which prevent it being broken down.

In healthy liver tissue the scars eventually melt away and are replaced by new normal tissue.

However, in diseased tissue this process does not happen. Instead the scar tissue proliferates, and spreads throughout the whole organ.

The Newcastle team showed that sulfasalazine could aid recovery by blocking the production of proteins that keep the scar tissue cells alive.

They plan to carry out trials in humans, but already believe the drug has the potential to provide an alternative to a liver transplant.

The drug will initially be given to heavy drinkers who have given up alcohol, but too late for their liver to recover naturally.

If this proves successful, the medicine will also be prescribed to alcoholics who continue to drink but show a determination to fight their addiction by reducing their intake.

Professor Derek Mann, who led the research, said just a 5% to 10% recovery of the organ could have a huge impact on quality of life.

Efforts needed

Professor Chris Day, head of Newcastle University's School of Clinical Medical Sciences, said the drug was likely to work best on people who had made some effort to kick their boozing habit.

But he said it offered a potential solution to the tricky ethical problem of offering people who abused alcohol a liver transplant.

Some believe it is wrong to use organs that are in very short supply on people who have not demonstrated their ability to reform their drinking.

Professor Day said: "In that situation you may not give somebody a transplant, but you are not going to stop them getting a tablet, particularly if it only costs £10 a week.

"Cirrhosis is the fifth highest cause of death in the UK today, and it would not be too optimistic to say this drug could halve that death rate."

Professor David Jones, another member of the Newcastle liver team, said he and his colleagues regularly saw patients in their twenties with severe liver disease.

He said: "There is no point at which an alcoholic patient won't benefit from stopping drinking, but now we can actually help the healing process."

Anne Jenkins, of the charity Alcohol Concern, said: "The last 20 years have seen a significant increase in rates of liver cirrhosis, particularly among the 34-45 age group.

"Research that could help to reverse harm is obviously to be welcomed, but this work is at an early stage, and more needs to be done."

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Bayer Initiates Phase III Trial of Regorafenib in Patients with Advanced Liver Cancer

Wednesday - May 15, 2013

Not intended for U.S. and UK Media

Berlin, May 15, 2013 – Bayer HealthCare today announced that the company has started to enroll patients in an international Phase III trial to evaluate the efficacy and safety of regorafenib for the treatment of patients with hepatocellular carcinoma (HCC) who have progressed on sorafenib treatment. Regorafenib is an oral multi-kinase inhibitor that inhibits various kinases within the mechanisms involved in tumor growth and progression – angiogenesis, oncogenesis and maintenance of the tumor microenvironment.

“With sorafenib being a major advance in the treatment of unresectable HCC, Bayer remains committed to developing other treatment options, as there is a high unmet medical need for patients with advanced liver cancer whose disease has progressed after treatment with sorafenib,” said Kemal Malik, MD, Member of the Bayer HealthCare Executive Committee and Head of Global Development. “This international Phase III trial further broadens Bayer’s extensive and ongoing clinical development program for regorafenib and underscores Bayer’s commitment to developing novel treatment options, particularly for patients with difficult-to-treat cancers.”

About the Phase III Study
The RESORCE [REgorafenib after SORafenib in patients with hepatoCEllular carcinoma] clinical trial is a randomized, double blind, placebo controlled, multicenter Phase III study of regorafenib in patients with hepatocellular carcinoma whose disease has progressed after treatment with sorafenib. The trial will enroll approximatehly 530 patients who will be randomized in a 2:1 ratio to receive either regorafenib plus best supportive care (BSC) or placebo plus BSC.

Patients will receive 160 mg regorafenib once daily, for 3 weeks on/1week off, or placebo. The primary endpoint of the study is overall survival, and secondary endpoints are time to progression, progression-free survival, objective tumor response rate and disease control rate. Safety and tolerability of the treatment groups will also be continously monitored.
The study will be conducted in North America, South America, Europe, Asia and Australia. For further information about the study, please visit www.clinicaltrials.gov.

About Hepatocellular Carcinoma
Hepatocellular carcinoma (HCC) is the most common form of liver cancer and is responsible for approximately 90 percent of the primary liver cancers in adults. Liver cancer is the seventh most common cancer in the world and the third leading cause of cancer-related deaths globally.
Major risk factors that can lead to the development of HCC include alcohol abuse, hepatitis B, hepatitis C, the use of anabolic steroids and some hereditary diseases. HCC is often hard to detect early because signs and symptoms do not usually appear until it is in its later stages, and thus the majority of patients diagnosed with HCC have advanced disease, and may not be eligible for potentially curative therapies.

About Regorafenib
Regorafenib is an oral multi-kinase inhibitor that targets oncogenesis, tumor angiogenesis and maintenance of the tumor microenvironment signaling by inhibiting multiple protein kinases. In preclinical studies, regorafenib has been shown to inhibit several angiogenic VEGF receptor tyrosine kinases that play a role in tumor neoangiogenesis (the growth of new blood vessels). It also inhibits various oncogenic and tumor microenvironment kinases including VEGFR 1-3, KIT, RET, PDGFR and FGFR, which individually and collectively impact upon tumor growth, formation of a stromal microenvironment and disease progression.

Regorafenib was approved under the name Stivarga® by the U.S. Food and Drug Administration (FDA) for the treatment of metastatic colorectal cancer (mCRC) in September 2012 and for the treatment of gastrointestinal stromal tumors (GIST) in February 2013. It was also approved in Japan for the treatment of advanced or recurrent CRC in March 2013. Bayer has also submitted for marketing approval of regorafenib for the treatment of mCRC in the EU in May 2012. In December 2012, Bayer submitted a filing in Japan for regorafenib for the treatment of GIST and has received priority review for this indication.

Regorafenib is a Bayer compound developed by Bayer and jointly promoted by Bayer and Onyx in the U.S. In 2011, Bayer entered into an agreement with Onyx, under which Onyx receives a royalty on all global net sales of regorafenib in oncology.

About Bayer HealthCare
The Bayer Group is a global enterprise with core competencies in the fields of health care, agriculture and high-tech materials. Bayer HealthCare, a subgroup of Bayer AG with annual sales of EUR 18.6 billion (2012), is one of the world’s leading, innovative companies in the healthcare and medical products industry and is based in Leverkusen, Germany. The company combines the global activities of the Animal Health, Consumer Care, Medical Care and Pharmaceuticals divisions. Bayer HealthCare’s aim is to discover, develop, manufacture and market products that will improve human and animal health worldwide. Bayer HealthCare has a global workforce of 55,300 employees (Dec 31, 2012) and is represented in more than 100 countries. More information at www.healthcare.bayer.com.

Our online press service is just a click away: press.healthcare.bayer.com
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Find more information at www.bayerpharma.com.

Forward-Looking Statements
This release may contain forward-looking statements based on current assumptions and forecasts made by Bayer Group or subgroup management. Various known and unknown risks, uncertainties and other factors could lead to material differences between the actual future results, financial situation, development or performance of the company and the estimates given here. These factors include those discussed in Bayer’s public reports which are available on the Bayer website at www.bayer.com. The company assumes no liability whatsoever to update these forward-looking statements or to conform them to future events or developments.

Hepatitis C Virus Therapy Update 2013

Current Opinion in Gastroenterology

Lisa C. Casey, William M. Lee

Curr Opin Gastroenterol. 2013;29(3):243-249.

Abstract and Introduction

Abstract

Purpose of review: We review here the recent literature regarding hepatitis C virus (HCV) therapy through January 2013. We discuss current therapies, targets for new therapies, and what might be expected in this rapidly changing field.

Recent findings: Boceprevir-based and telaprevir-based triple therapy with pegylated interferon and ribavirin marked the beginning of a new era in HCV therapy for genotype 1 patients. New direct-acting antivirals (DAAs) are being developed and new antiviral drug targets are being explored. New combination treatment regimens are expected to emerge soon and there is hope for interferon-free regimens.

Summary: The standard of care for treatment of HCV genotype 1 changed dramatically with the approval of two new DAA drugs – telaprevir and boceprevir – for use in pegylated interferon-based and ribavirin-based triple therapy in mid-2011. Experience has shown improved response rates and treatment durations for many patients with genotype 1 HCV infection. However, persistent limitations to HCV treatment still exist for patients with prior treatment failure and comorbid conditions and patients on newer therapies suffer additional therapy-limiting side effects and drug–drug interactions. Genetic testing may provide some guidance but additional options for therapy are still needed for HCV. Many new drugs are currently under investigation and there is hope that effective and well tolerated interferon-free regimens may become a part of future therapy.

Introduction

An estimated 130–170 million people are infected with hepatitis C worldwide leading to significant morbidity, mortality, and financial burden on healthcare.^[1] Out of 100 people who contract the infection, 75–85% will develop chronic infection, 60–70% will develop chronic liver disease, 5–20% will develop cirrhosis over the course of their chronic infection, and 1–5% will die of complications including hepatocellular carcinoma (HCC).^[1,2] The majority of the infected population in the United States, an estimated 3.2–3.7 million people, are believed to have been born between 1945 and 1965 and likely contracted the virus when transmission rates were highest in the 1970s and 1980s.^[3,4] Hepatitis C virus (HCV) has a long and relatively symptom-free incubation period prior to causing serious illness. Although the contribution of blood product screening, disposable medical equipment, and public health education efforts over the years has led to a decrease in the incidence of HCV in the United States, an estimated 65–75% of currently infected individuals in the United States are unaware of their infection. The consequences of these undiagnosed and untreated chronic infections are expected to be staggering as this population ages with predictive models suggesting a two-fold increase in HCV-related deaths with direct medical costs exceeding $6.7 billion between 2010 and 2019^[5] and, without intervention, a four-fold rise in the incidence of end-stage liver disease related to hepatitis C within the next 20 years.^[6] An effort to capture these patients has led to the recent Centers for Disease Control and Prevention recommendations for birth cohort screening of the population born between 1945 and 1965 in the United States.^[4]

Outside of the United States, many other countries worldwide face significant HCV infection rates. Despite aggressive programs toward education, care, and treatment over the last 10 years, Egypt faces the largest burden of HCV infection in the world with a 10% prevalence of chronic hepatitis C infection among persons aged 15–59 years, predominantly genotype 4.^[7] In many parts of the world the virus remains unchecked because of continued unsafe medical practices, lack of public health education, and lack of funding for research and treatment. Perz et al.^[8] looked at 11 WHO-based regions in 2006 and estimated that globally 27% of cirrhosis was attributable to HCV and 25% of HCC was attributable to HCV. In many countries and populations, only a small number of patients with known infection actually receive treatment and yet successful treatment has been shown to have a significant impact on outcomes.^[6,9] A sustained virological response (SVR) to hepatitis C therapy reduces liver-related as well as all-cause mortality for patients with hepatitis C^[3,8] including a 70–80% reduction in overall liver-related mortality and hepatic decompensation and a 75% reduction in risk of HCC at all stages of fibrosis.^[4,10]

Until 2011, the historically accepted standard therapy with pegylated interferon and ribavirin produced an SVR rate of approximately 40–50% for genotype 1 patients and higher rates up to 80% for alternate genotypes after 24–48 weeks of therapy.^[11] The limitations of this therapy are well recognized. Pregnant patients or those with advanced renal disease are contraindicated from using ribavirin. Likewise, interferon therapy excludes patients with autoimmune diseases, uncontrolled depression and mental illness, decompensated liver disease (child turcotte pugh > 6) or decompensated cardiac or pulmonary disease. Patients experienced frequent side effects and those failing therapy due to relapse, non or null response had few options. This led to aggressive research into additional treatment targets and ways to predict patient response to treatment.

Viral Structure

What was first known as non-A, non-B hepatitis was designated hepatitis C in 1989 by Michael Houghton and scientists at Chiron Corporation while searching for the blood-borne cause of hepatitis in transfusion recipients (see Fig. 1).^[12] Hepatitis C is a single-stranded RNA flavivirus of the hepacivirus genus. Of the six genotypes, genotype 1 is the most prominent in the United States and Europe. The virus lacks proofreading ability leading to significant genetic variation, historically making drug development against the virus challenging. When the virus enters a liver cell, it releases its RNA and is translated into a poly-protein containing structural and nonstructural regions. The poly-protein is processed by proteases into several polypeptides with different functional roles in the virus life cycle. The virus is replicated with the help of a polymerase and then assembled, transported, and released from the cell. The nonstructural region codes for the polypeptides NS2, NS3, NS4A, NS4B, NS5A, and NS5B. All are potential targets for drug therapy. Initial cleavage of the poly-protein is performed by the NS3/NS4A protease, which seems to be highly conserved across most strains, and, without which, the HCV life cycle cannot proceed.^[13] This region became the first therapeutic target for direct-acting antiviral (DAA) therapy, the NS3/NS4 protease inhibitors telaprevir and boceprevir.

Figure 1.

Viral structure and genome demonstrating potential therapeutic targets. Reproduced with permission from.[12] HCV, hepatitis C virus.

The Era of Triple Therapy

The creation of the new standard 'triple therapy' with the DAA medications has led to significant improvements in the response rates for patients with genotype 1 HCV, with SVR rates as high as 63–75% and reduction in duration of therapy by half for many patients based on response-guided therapy (RGT). The first Food and Drug Administration (FDA)-approved protease inhibitors, telaprevir and boceprevir, are designed to mimic the natural NS3/NS4A protease substrate in genotype 1 HCV, therefore inhibiting the onset of the replication process. The successes, failures, and new challenges of triple therapy have become well known. Although the advent of triple therapy has dramatically improved outcomes for many, therapeutic options for HCV are still far from optimal. Many new side effects have been encountered with creative management strategies developed, drug interactions have taken on new importance and issues with resistance and intolerance persist. With the explosion of research and development of newer DAA and additional therapeutic targets, we are at the very beginning of a new era in HCV therapy. A review of the lessons learned from the beginning will be important as we move forward.

First-generation Protease Inhibitors: Lessons From Telaprevir and Boceprevir

Telaprevir efficacy was initially proven in multiple large multicenter trials including protease inhibition for viral evaluation-1 (PROVE-1), PROVE-2, PROVE-3, ADVANCE, REALIZE, and illustrating the effects of combinatherapy with telaprevir (ILLUMINATE).^[13–16] The importance of ribavirin was confirmed by demonstration of significant viral breakthrough and relapse after therapy in patients in a pegylated interferon and telaprevir study arm without ribavirin. These early trials developed and confirmed the utility of RGT, suggesting that a shortened duration of therapy was acceptable for patients meeting certain criteria and 24 weeks of telaprevir-based therapy was noninferior to 48 weeks of triple therapy in patients meeting appropriate criteria. Differences have been observed in treatment failure rates between genotypes 1a and 1b and in various difficult-to-treat groups. African–Americans, those with high-viral loads, bridging fibrosis or cirrhosis demonstrated somewhat improved rapid viral response with new agents but responses are still decreased compared with those observed in naive, noncirrhotic patients.^[14–17]

Conceptually, the Peg-interferon/ribavirin lead-in was introduced to bring the baseline viral load down prior to starting boceprevir and, in turn, decrease the emergence of drug-resistant mutations. SVR was similar in the 28-week and 48-week groups that demonstrated at least a 1.5 log drop in viral load after the 4-week lead-in therapy phase. Patients in the 28-week triple therapy arm that did not demonstrate the 1.5 log drop after lead-in showed a poor SVR of 30% or less at 28 weeks compared with the corresponding 48-week group. The overall conclusion was that RGT based on 4-week lab values would help predict the best duration of treatment.^[18] Serine protease inhibitor therapy trial-2 (SPRINT-2) stratified black and non-black patients into different arms and again demonstrated persistently lower SVR rates for black patients versus non-blacks, suggesting interferon resistance continued to play a role.^[19] Additional studies suggest that the use of interleukin (IL)-28 genotyping (rs 12979860) may also identify patients who are more likely to qualify for shorter treatment durations in RGT with boceprevir.^[19,20] Thus, interferon responsiveness is important in prediction of response to triple therapy; patients with a poor response to interferon might be best served by waiting for improved future therapies.

Limitations of First-generation Direct-acting Antiviral Therapy

Although the advent of triple therapy with boceprevir and telaprevir has improved response rates and treatment durations for many patients with genotype 1 disease, the phase 3 clinical trials demonstrated that many still do not achieve SVR. In addition, drug–drug interactions limit use, the high pill burden makes compliance difficult and resistance is still a real threat with unclear future implications. New rashes and anorectal symptoms are seen with telaprevir and moderate-to-severe anemia is common in both regimens.^[16,19,21] In December 2012, a black box warning was added to telaprevir labeling in light of some rashes resulting in death.^[22]

What is Needed: Goals for the Future

Traditionally HCV therapy has been nonspecific in its therapeutic target. Interferon activates the immune system and inhibits viral replication whereas ribavirin is a nonspecific antiviral that may inhibit viral replication but also aid in viral clearance though its true function against HCV is elusive.^[23,24] Newer therapies directed against specific viral and host targets appear to have greater potential for success.

Epidemiologists have produced a long list of barriers to HCV treatment including goals for future HCV medications including: improved tolerance, high potency, favorable safety profile, high barrier to resistance, all oral regimen, pan-genotypic, favorable pill burden, short duration, few drug interactions, available for cirrhosis, HIV, mental illness, and affordable.^[5,9] For the first time, ongoing research suggests that many of these goals may be realistic.

Understanding Direct-acting Antiviral Resistance is Important for the Future

Drug resistance was noted in some form with both telaprevir and boceprevir in the early protease inhibitor trials, impacting the final structure of treatment protocols. Specifically, ribavirin use is required by all protocols and genotypic subtypes 1a and 1b demonstrate a recognizable difference in rates of SVR. The findings are explained by the very low genetic barrier to resistance of protease inhibitors as a class, defined as the number of amino acid substitutions required to confer full resistance to a drug.^[25,26] In general, DAAs with a low genetic barrier to resistance require only 1–2 amino acid substitutions for high resistance and DAAs with a high barrier to resistance usually require 3–4 amino acid substitutions in the same region. Telaprevir resistance is recognized to most frequently be represented by mutation R155K. The R-K change requires only one nucleotide change in genotype 1a, whereas genotype 1b requires two nucleotide changes. The amino acid target sequence of the NS3 region differs significantly between HCV genotypes (explaining why telaprevir and boceprevir have efficacy limited to genotype 1) and resistance can develop easily with few mutations.^[25] The barrier to genetic resistance of DAA in development will be a critical factor in the success of future regimens.

Resistance-associated amino acid variants (RAVs) have been found in treatment-naive HCV as well as after drug exposure, thought to result from genetic variation inherent in the virus itself and selective pressure from drugs. Given as monotherapy, most DAAs rapidly select for HCV variants with reduced drug susceptibility resulting in virological failure and treatment rebound.^[27] Although protocols instruct against monotherapy, reaffirmation of the mandate that these drugs not be used alone is important. Cross-reactivity has been shown in RAV between telaprevir and boceprevir and there is the theoretical risk for development of resistance to several protease inhibitors with injudicious use of one of the current regimens. Careful monitoring of stopping rules is essential in current therapies, particularly in the setting of treatment of prior null responders.^[28] Fortunately, there are multiple different targets for therapy with differing genetic barriers to resistance. On the basis of what we have learned to this point, combination therapy will be the rule in the future.

New Drugs in Development

In addition to boceprevir and telaprevir, many new DAA and host-targeted drugs are in development (Table 1).^[23–28]

Table 1. New hepatitis C drugs in development

NS3/4A protease inhibitors	NS5A	NS5B polymerase nucleos(t)ide	NS5B	NNI Host targets
Asunaprevir	Daclatasvir	Mericitabine	Tegobuvir	Alisporovir
Vaniprevir	ABT-267	Sofasbuvir	Filibuvir	Mirvirsen
Danoprevir	GS-5885	IDX184	BI-207127
MK-5172	PPI-461	PSI-938	VX-222	lambda IFN
BI-201335	BMS791325	Setrobuvir
Simeprevir		ABT-333
Tibotec	INX-189
ABT-450

Compiled from [23–28].

Protease Inhibitors: The Next Generation

Despite their limitations, protease inhibitors have high antiviral efficacy and will play an important role in future therapies. Newer protease inhibitors in development: asunaprevir, danoprevir, vaniprevir, MK-5172, BI-201335, and simeprevir are expected to have improved tolerance and safety profiles and will likely be used in combination with pegylated interferon and ribavirin or in newer DAA combination regimens in the future.

Polymerase Inhibitors: NS5B

Polymerase inhibitors interfere with viral replication by binding to the NS5B RNA-dependent RNA polymerase. Their success has been demonstrated extensively in phase 1 and 2 trials, and they are expected to play an important role in newer DAA combination therapy regimens. The class comprises two types – nucleos(t)ide inhibitors and non-nucleotide inhibitors (NNIs). Nucleos(t)ide analogue inhibitors are active site inhibitors that mimic the natural substrates of the polymerase, being incorporated into the RNA chain and causing direct chain termination. As the active site of NS5B is highly conserved, these are potentially active against all the different genotypes. In addition, as amino acid substitutions in every position of the active site may result in loss of function, resistance to nucleos(t)ide analogue inhibitors is usually low. Mericitabine and sofosbuvir both have demonstrated convincing data in clinical trials.

Non-nucleoside inhibitors, on the contrary, bind to several discrete sites outside of the polymerase active center, which results in a conformational protein change before the elongation complex is formed – essentially inhibiting the polymerase from a distance. Resistance is more frequent with NNIs as NS5B is structurally organized into multiple different domains with at least four different binding sites. Mutations at the individual binding sites do not necessarily cause loss of function of the polymerase.^[25] Drugs in this category are tegobuvir, filibuvir, BI-207127, VX-222, ANA598, ABT-333.

NS5A Inhibitors

NS5A is a membrane-associated phosphoprotein involved in HCV virion production and the viral life cycle. Daclatasvir, the first in its class NS5A inhibitor, exhibits high potency and is expected to have a broad range of genotypic coverage; it is synergistic with other DAAs. Several others are in development including ABT-267, GS-5885, PPI-461.^[25,28]

Host-targeted Therapies

Several drugs are in development against host targets. Cyclophilin inhibitors such as the cyclophilin A binding molecule alisporivir appear to have potent anti-HCV activity and have broad genotype activity for types 1–4. Alisporivir appears to inhibit HCV viral replication by interfering with the interaction between cyclophilin A and NS5A. In early trials with pegylated interferon and ribavirin, an SVR rate into the 70% range was seen with 24 weeks of once daily therapy and benefits have been confirmed in genotypes 2 and 3, with particular success against genotype 3 and a very high barrier to resistance.^[23] An additional host-targeted agent is the subcutaneously administered drug, mirvirsen, which specifically targets the liver-specific micro-RNA miR-122 that is involved in gene expression and HCV viral replication, producing dramatic suppression of HCV viremia without evidence of RAV or significant side effects in early trials. New interferons have also been explored. Native human interferon lambda proteins are generated by the immune system in response to viral infection. This interferon family has been found to have antiviral activity against HCV. The interferon and its receptor are both expressed at high levels by hepatocytes but not all tissues suggesting that this reagent could have tissue specific effects, potentially equating to reduced toxicity compared to current experience with α-interferon.^[23] This could be a better tolerated alternative to interferon α until oral regimens are available.

What About Interferon-free Regimens?

Interferon-free regimens are widely being tested in clinical trials with encouraging results. The following selected trials demonstrate how rapidly progress is being made. Beginning in 2010, studies demonstrated the potential for antiviral efficacy of an all-oral regimen using combinations of drugs with different targets.

Interferon-free regimen for the management of HCV-1 (INFORM-1) was a phase 1 proof of concept study from 2010 using combination DAA without interferon.^[27] Danoprevir, an NS3/4A protease inhibitor, and RG7128 (later named mericitabine), a NS5B nucleoside polymerase inhibitor, were given for up to 13 days in multiple different dosing arms to assess the ability of an interferon-free regimen to suppress viral load. After the treatment period, all patients subsequently were given standard of care pegylated interferon and ribavirin for 48 weeks. Overall, the DAA combination therapy was well tolerated, and there were no treatment-related study withdrawals or dose reductions during the treatment period. Most common adverse event was headache. The DAA combination regimen showed very potent activity against HCV in all participants, including previous null responders giving encouragement that interferon-free all DAA regimens are possible. Of note, patients with cirrhosis were excluded.

SOUND-1 and SOUND-2 trials included an NS3/4A protease inhibitor (BI-201335) and an NNI NS5B polymerase inhibitor (BI-207127) and ribavirin to demonstrate proof of potent antiviral activity against HCV with rapid viral response rates of 73–100% dependent on dosing. Genotype 1b responded more favorably than 1a and the ribavirin-sparing arm in the later trial showed reasonable but substantially lower response rates. Final results were presented in abstract form at the American Association for the Study of Liver Diseases (AASLD) Liver Meeting 2012.^[29] Patient results were randomized by genotype 1a versus 1b and by IL-28 genotype CC/CT/TT. Ribavirin arms with variable DAA dosing demonstrated a range in SVR12 (SVR after only 12 weeks off therapy), of 52–69% but only 39% in ribavirin-free arms. Genotype 1b responded better than 1a and IL-28 appeared to be an independent predictor of SVR. All IL-28 genotype of 1b and IL-28 CC 1a patients demonstrated SVR 12 rates as high as 84% with the all-oral regimen.

More recently, exciting results from the phase 2 ELECTRON trial were reported.^[30] Sofosbuvir (formerly known as GS-7977) NS5B polymerase inhibitor in a once daily dose was combined with ribavirin for 12 weeks, pegylated interferon and ribavirin for 4, 8, or 12 weeks in naive patients with genotypes 2 or 3 or sofosbuvir monotherapy for 12 weeks in naive patients with genotypes 2 or 3. An additional group of 35 genotype 1 patients was enrolled, 25 naive patients and 10 prior nonresponders who were also treated with sofosbuvir and ribavirin for 12 weeks. After 24 weeks of therapy, all naive genotype 2 and 3 patients on combination therapy had an SVR at 24 weeks (100%). SVR was seen in only 60% of the genotype 2 and 3 patients on monotherapy. Among genotype 1, treatment-naive patients demonstrated 84% SVR and prior nonresponders fared less well with an SVR of only 10%. Sofosbuvir appears to be well tolerated and to have a high barrier to resistance. This study suggests a new DAA option may soon be available for naive patients with genotype 1, 2, and 3; however, ribavirin still plays a role in maintenance of an antiviral response.^[30]

Another new phase 2 clinical trial was found to show even better responses in genotype 1 patients. ABT-450 (an NS3 protease inhibitor) combined with low-dose ritonavir, ABT-333 (a non-nucleoside NS5B polymerase inhibitor), and ribavirin were used in varying doses in treatment-naive and experienced patients excluding those with cirrhosis for 12 weeks. Treatment-naive patients demonstrated an SVR12 of 93–95% depending on dose and treatment experienced patients an SVR12 of 47%. Some viral breakthrough and resistance was noted during treatment in the prior nonresponder population and the study suggests this population will need a modified DAA regimen as extending duration would not have changed outcome. Overall, this 12-week combination therapy may be an effective future therapy for HCV genotype 1.^[31]

Conclusion

We are once again preparing for a dramatic paradigm shift in approach to HCV infection. Worldwide, the epidemic proportions of HCV are coming to light both in the efforts of healthcare workers and governments in the underdeveloped world and in the burden from untreated and undiagnosed disease in the developed world. Numerous new drugs targeting various aspects of the HCV life cycle and the host are in development and clinical trials. Overall, combination therapies will be the rule. New combinations of DAA have synergistic effects, decrease the risk of resistance, and improve antiviral efficacy, are effective in different genotypes and have a favorable safety profile. Despite universal hope for all-oral regimens, pegylated-IFN is still in the literature. Many phase 1 and 2 clinical trials are still designed to demonstrate the safety of new DAA in combination with a pegylated interferon and ribavirin backbone and though the best response rates in interferon containing regimens still tend to be in favorable genotypes or IL-28 CC patients, the important benefit in these combinations is much shorter treatment duration of 12 weeks. Interferon-free combination regimens appear to be on the horizon, providing a new option in particular for patients with non-genotype 1 HCV, but there will still be treatment failures and resistance issues to be overcome, particularly in the treatment experienced population.

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Recent advances in the treatment of hepatocellular carcinoma

Curr Opin Gastroenterol. 2013; 29(3):285-92 (ISSN: 1531-7056)

Padhya KT; Marrero JA; Singal AG
Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern, Dallas, Texas, USA.

PURPOSE OF REVIEW: To provide an up-to-date summary of the recent advances in therapies for hepatocellular carcinoma (HCC).

RECENT FINDINGS: Surgical resection, liver transplantation, and local ablative therapies such as radiofrequency ablation offer potential cure for tumors detected at an early stage in well selected patients. The role of adjuvant or neoadjuvant therapy is being investigated, but there is no clear evidence supporting its routine use currently. Some have proposed expanding size criteria for transplantation or downstaging tumors detected beyond an early stage, although benefits must be weighed against harms to others on the waiting list. For intermediate-stage HCC, transarterial chemoembolization is the mainstay of treatment, although there is increasing evidence supporting a role for transarterial radioembolization. For advanced HCC, sorafenib is the only systemic therapy to significantly prolong survival in patients with Child A cirrhosis and good performance status. Ongoing trials are evaluating the role of other targeted therapies in patients with advanced HCC.

SUMMARY: There have been advances in HCC treatment options over the last couple of years and there are now potential therapies for most patients with any stage of disease. Treatment decisions must be individualized after accounting for factors such as degree of liver dysfunction and patient performance status.

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End-stage liver disease complications

Curr Opin Gastroenterol. 2013; 29(3):257-63 (ISSN: 1531-7056)

Rahimi RS; Rockey DC
aAnnette C. and Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, Texas bDepartment of Internal Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.

PURPOSE OF REVIEW: Chronic liver disease causes significant morbidity and mortality because of any number of complications including hepatic encephalopathy, ascites, hepatorenal syndrome (HRS), and esophageal variceal hemorrhage (EVH).

RECENT FINDINGS: Predictors of response to lactulose, probiotics, and L-ornithine-L-aspartate therapy in minimal hepatic encephalopathy (MHE) have been reported. Although rifaximin was slightly more effective than lactulose in the maintenance of remission and decreased re-admission in patients with MHE, it was not as cost-effective as lactulose. Beta-blockade has been associated with paracentesis-induced circulatory dysfunction. Those who respond to nonselective beta-blockers have a predictable overall lower probability of developing ascites and HRS. Noradrenaline was as effective as terlipressin for the treatment of type 1 HRS and was less costly. Hemorrhagic ascites, defined as an ascitic fluid red blood cell (RBC) count of at least 10 000/μl, appeared to be a marker for poor outcome in patients with cirrhosis. In patients with acute EVH, band ligation, pharmacologic vasoconstrictors, and antibiotics are effective; notably, intravenous proton pump inhibitor therapy in lieu of vasoconstrictors achieved similar hemostatic effects with fewer side-effects.

SUMMARY: Refinement in the clinical management strategies for patients with cirrhosis and its complications appear to continue to contribute to improved patient outcomes.

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Screening Events Promote Hepatitis Testing and Prevention during National Hepatitis Awareness

Hepatitis B and C are the greatest causes of liver cancer in America, but can be prevented or treated;
Screening events and PSAs being coordinated in New York City, San Francisco and Los Angeles

May 14, 2013 12:15 PM Eastern Daylight Time

SAN FRANCISCO & LOS ANGELES & NEW YORK--(BUSINESS WIRE)--During National Hepatitis Awareness Month this May, Hep B Free San Francisco, Asian Week Foundation, and National Viral Hepatitis Roundtable are helping to coordinate hepatitis screenings and a new public service announcement to highlight prevention of hepatitis B and C (HBV/HCV) disease, which together cause almost all liver cancers worldwide.ⁱ Screening events featured in the PSA are being held in three of the largest metro areas affected by viral hepatitis: New York, NY, Los Angeles, CA, and San Francisco, CA.

“We are excited to see this first-ever national collaboration with local communities, healthcare groups and the media to promote testing for viral hepatitis and the prevention of liver disease in our communities”

Viral hepatitis is a leading infectious cause of death in the U.S. To combat the epidemic, the U.S. Department of Health and Human Services created an Action Plan in 2011 for the Prevention, Care and Treatment of Viral Hepatitis. The launch of Hepatitis Awareness Month, observed in May, National Hepatitis Testing Day, observed May 19, and National Hispanic Hepatitis Awareness Day, observed on May 15, have resulted in a growing number of events being organized by local communities in cities around the country to highlight hepatitis prevention.

This year, events in New York City will start on Tuesday, May 14 with a press conference on the steps of City Hall organized by National Hispanic Hepatitis Awareness Day, the New York Hep C Task Force and the New York Hep B Coalition. Los Angeles will hold a media event and community rally on Friday May 17 organized by Hep B Free Los Angeles and the Hep C Task Force of Los Angeles. San Francisco will hold a large pubic screening event and press conference on Saturday May 18 organized by San Francisco Hep B Free and the San Francisco Hep C Task Force. Other events will also be taking place throughout the country in observance of the awareness and testing days.

The televised awareness commercials will air from May 8 to May 19 in the New York, Los Angeles and San Francisco media markets. The commercials feature a call for hepatitis testing as a way to prevent liver cancer and include a unique URL for each city that links to local hepatitis resources and screening events.

“We are excited to see this first-ever national collaboration with local communities, healthcare groups and the media to promote testing for viral hepatitis and the prevention of liver disease in our communities,” said Ted Fang, Executive Director of AsianWeek Foundation. AsianWeek Foundation and SF Hep B Free spearheaded the three-city coordination and worked with the National Viral Hepatitis Roundtable to develop the television awareness commercials.

“This is a wonderful multi-faceted approach for educating the public about the need for viral hepatitis testing,” said Martha Saly, Executive Director of National Viral Hepatitis Roundtable. “We are proud to be part of this coalition and building private/public partnerships to end viral hepatitis liver disease in America.”

“Far too many Americans – approximately four million -- are infected with hepatitis B or hepatitis C, and the majority of those individuals don’t know it,” said Howard K. Koh, M.D., M.P.H., Assistant Secretary for Health, U.S. Department of Health and Human Services. “The HHS National Viral Hepatitis Action Plan promotes prevention, screening, care and treatment to tackle this silent epidemic.”

The majority of liver cancers in the world are attributable to chronic infections of HBV and/or HCV. Primary prevention of HBV infection includes vaccination. HCV infection is potentially preventable through public health measures, including screenings.ⁱⁱ Many will die from liver cancer if they do not receive the proper care. Several minorities are disproportionately impacted by hepatitis. For example, Hepatitis B is the greatest health disparity for both African immigrants and Asian Americans affecting approximately 10% of both groups.

In 2012, approximately 4,300 Hispanics will be diagnosed with liver cancer, and about 2,700 will die from the disease. Liver cancer incidence rates in the US are about twice as high in Hispanics as in non-Hispanic whites.ⁱⁱ

About Hepatitis C Virus (HCV)

Hepatitis C virus (HCV) is the most common chronic blood-borne viral infection and the most common cause of chronic liver disease in the United States. An estimated 3.2 million Americans are infected with HCV, and are at risk for developing cirrhosis and liver cancer. Most persons who have HCV are not aware they are infected, and most with acute infection (60%-70%) show no symptoms. Approximately three of four infected persons were baby-boomers, born between 1945-1965. HCV is responsible for more than 15,000 deaths in the United States every year. In Los Angeles County, an estimated 180,000 persons are infected with HCV, and rates of HCV infection in the general population are estimated at 1.8%, 3.2% among persons born 1945-1965, and as high as 67.8% among injection drug users.

There is currently no vaccine to protect against Hepatitis C infection.

HCV is transmitted by exposure to infected blood. Sexual transmission is possible, but not common. It is most common among people who have injected drugs at some point during their lives. People who have received blood transfusions or organ transplants before widespread screening of the blood supply began in 1992 are also at risk. Others at risk include children born to HCV-positive women, sexual partners of persons with HCV and health care or emergency workers. To prevent HCV infection, only sterile needles and equipment should be used, and personal items, such as toothbrushes, razors or nail clippers should not be shared.

Among HIV-affected persons, one in four are infected with HCV; liver disease is a leading cause of death for persons with HCV. Co-infection rates with HCV are believed to be as high as 40%. An estimated 60-90% of people who contracted HIV from injection drug use also are infected with HCV.

About Hepatitis B Virus (HBV)

The Hepatitis B Virus (HBV), which attacks the liver, is 100 times more infectious than HIV/AIDS. HBV can cause lifelong (chronic) infection, cirrhosis (scarring) of the liver, liver cancer/failure, and death. The U.S. Centers for Disease Control and Prevention (CDC) recommends routine screening and vaccination for HBV in all individuals from high prevalence regions, including Asia, Africa, and parts of South America. Screening can prevent HBV transmission, suffering, and death.

Of the 800,000 to 1.4 million with chronic hepatitis B in United States, and 25% will die of HBV-related liver diseases if not treated. Liver cancer is one of the most common cancers in AAPIs in California. Among men, it is the most common cancer in Cambodians and Laotians, 2^nd most common in Vietnamese, 4^th in Chinese, Filipino and Native Hawaiians, and 5^th in Koreans and Pacific Islanders. Among women, liver cancer is the 5^th most common cancer in Cambodians, Laotians and Vietnamese, and is also common in other AAPI women. In the U.S., AAPIs have the highest rate of liver cancer of any racial/ethnic group. Also, 80% of the HBV perinatal caseload in California, and within Los Angeles County, are AAPI women and household contacts. HBV is one of the greatest health disparities between AAPIs and the general US population (which has less than 1% prevalence of chronic HBV infection).

ⁱ American Cancer Society: http://www.cancer.org/acs/groups/cid/documents/webcontent/003114-pdf.pdf
ⁱⁱ American Cancer Society: http://www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/document/acspc-034778.pdf

Contacts

Hep B Free San Francisco
Genevieve Jopanda, 415-913-0217
genevieve@sfhepbfree.org

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Achillion Appoints Dr. David Apelian as Chief Medical Officer and Expands Clinical Operations Team

May 15, 2013

NEW HAVEN, Conn., May 15, 2013 (GLOBE NEWSWIRE) -- Achillion Pharmaceuticals, Inc. (Nasdaq:ACHN) today announced the appointment of David Apelian, M.D., Ph.D., MBA, to the position of Executive Vice President and Chief Medical Officer, effective May 28, 2013. Dr. Apelian wll assume responsibility for the clinical development of Achillion's portfolio of compounds to treat HCV.

In addition, Achillion also announced today the expansion of its clinical operations group with the recent addition of Kevin Kucharski, formerly head of clinical operations at Pharmasset, who will serve as Senior Vice President of Clinical Operations.

"We are delighted that David is bringing his wealth of hepatitis and drug development expertise to Achillion. His operational and regulatory experience, highlighted by the regulatory approval of antivirals such as interferon alpha-2b/ribavirin and entecavir, will greatly benefit Achillion as we accelerate our development plans and seek to initiate registrational studies with sovaprevir and ACH-3102 during the latter part of next year," commented Michael D. Kishbauch, President and Chief Executive Officer of Achillion.

Dr. Apelian commented, "It is a very exciting time for me to be joining Achillion as Chief Medical Officer, and I look forward to further accelerating the development of the all-oral, interferon-free regimens containing sovaprevir and ACH-3102 for the treatment of chronic HCV."

Mr. Kishbauch also stated, "As Achillion continues its maturation into a late-stage biopharmaceutical company, the addition of both Kevin and David will expand our bandwidth, providing critical expertise and the support necessary for our HCV clinical development programs and our planned Phase 3 development."

David Apelian, M.D., Ph.D., MBA

Dr. Apelian brings to Achillion more than 13 years of industry experience from Bristol-Myers Squibb, Schering Plough and GlobeImmune where he focused on hepatology and infectious disease clinical development. Dr. Apelian was Clinical Director in the Infectious Diseases Group at Bristol-Myers Squibb (BMS), serving as medical co-lead for the clinical development and NDA submission of entecavir for chronic hepatitis B viral infection (HBV). Prior to BMS, Dr. Apelian served as Clinical Director in the Department of Hepatology/Gastroenterology at Schering Plough, coordinating a supplemental NDA filing for interferon alpha-2b and ribavirin for the treatment of pediatric patients with chronic hepatitis C viral infection (HCV). Most recently, Dr. Apelian served as Senior Vice President of Research and Development and Chief Medical Officer at GlobeImmune, where he was responsible for clinical development, regulatory affairs, clinical immunology, development of companion diagnostics, as well as target discovery and preclinical research.

Dr. Apelian completed his residency training in Pediatrics at New York Hospital, Cornell Medical Center. He received his M.D. from the University of Medicine and Dentistry of New Jersey, and his Ph.D. in Biochemistry and B.A. from Rutgers University. He also holds an M.B.A. from Quinnipiac University

Kevin Kucharski

Mr. Kucharski comes to Achillion with more than two decades of clinical operations expertise, with a focus on conducting U.S. and global clinical trials, ranging from Phase 1 through Phase 4. Prior to joining Achillion, Mr. Kucharski was Vice President of Clinical Operations at Pharmasset since 2007, and then at Gilead Sciences following their acquisition of Pharmasset. While at Pharmasset, Mr. Kucharski provided effective oversight and execution of various global clinical development projects including PSI-7977 and PSI-938. Prior to Pharmasset, Mr. Kucharski was Senior Director of Clinical Operations at Altana Pharma US, a Nycomed Company, where he established the Clinical Operations group. Prior to that, Mr. Kucharski held positions of increasing responsibility in Clinical Operations at Schering-Plough Research Institute. Mr. Kucharski was awarded his B.S. in Biology Research from the University of Scranton.

About HCV

The hepatitis C virus is the most common cause of viral hepatitis, which is an inflammation of the liver. It is currently estimated that more than 170 million people are infected with HCV worldwide including more than 5 million people in the United States, more than twice as widespread as HIV. Three-fourths of the HCV patient population is undiagnosed; it is a silent epidemic and a major global health threat. Chronic hepatitis, if left untreated, can lead to permanent liver damage that can result in the development of liver cancer, liver failure or death. Few therapeutic options currently exist for the treatment of HCV infection. The current standard of care is limited by its specificity for certain types of HCV, significant side-effect profile, and injectable route of administration.

About Achillion Pharmaceuticals

Achillion is an innovative pharmaceutical company dedicated to bringing important new treatments to patients with infectious disease. Achillion's proven discovery and development teams have advanced multiple product candidates with novel mechanisms of action. Achillion is focused on solutions for the most challenging problems in infectious disease, including HCV and resistant bacterial infections. For more information on Achillion Pharmaceuticals, please visit www.achillion.com or call 1-203-624-7000 begin_of_the_skype_highlighting 1-203-624-7000 end_of_the_skype_highlighting.

Forward-Looking Statements

This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other important factors that could cause actual results to differ materially from those indicated by such forward-looking statements, including statements with respect to: the potency, safety, tolerability, effectiveness and other characteristics of sovaprevir and ACH-3102; Achillion's expectations regarding timing for the commencement, completion and reporting of results of its -007 clinical trial of sovaprevir and ACH-3102 in combination with ribavirin, as well as with respect to the advancement into later stages of its clinical studies; and the expected contributions of Dr. Apelian and Mr. Kucharski and the planned expansion of the clinical operations group. Among the factors that could cause actual results to differ materially from those indicated by such forward-looking statements are risks relating to, among other things Achillion's ability to: replicate in later clinical trials positive results found in earlier stage clinical trials of sovaprevir, ACH-3102 and its other product candidates; advance the development of its drug candidates under the timelines it anticipates in current and future clinical trials; obtain necessary regulatory approvals; obtain patent protection for its drug candidates and the freedom to operate under third party intellectual property; establish commercial manufacturing arrangements; identify, enter into and maintain collaboration agreements with appropriate third-parties; compete successfully with other companies that are seeking to develop improved therapies for the treatment of HCV; manage expenses; successfully execute on its business plans and strategies; and raise the substantial additional capital needed to achieve its business objectives. These and other risks are described in the reports filed by Achillion with the U.S. Securities and Exchange Commission, including its Annual Report on Form 10-K for the fiscal year ended December 31, 2012 and its subsequent SEC filings.

In addition, any forward-looking statement in this press release represents Achillion's views only as of the date of this press release and should not be relied upon as representing its views as of any subsequent date. Achillion disclaims any obligation to update any forward-looking statement, except as required by applicable law.

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