June 10, 2013

Widespread Ignorance of Medication That Prevents HIV

Fran Lowry

Jun 10, 2013

Many teens and young adults at high risk for HIV in Washington, DC, would be willing to take pre-exposure prophylaxis every day to prevent infection, if only they were aware that such a thing existed.

In a study conducted to ascertain knowledge, acceptability, and willingness to use prophylaxis in sexually active at-risk people, only 10% said they had ever heard of it.

And when they learned that medication could protect them from HIV infection, most said they would take it, if offered by their healthcare provider.

The findings were presented at the 8th International Conference on HIV Treatment and Prevention Adherence in Miami, Florida. The meeting was jointly sponsored by the International Association of Physicians in AIDS Care, the National Institute of Mental Health, and the Post Graduate Institute for Medicine.

"As our study showed, there is very limited knowledge of pre-exposure prophylaxis overall," lead investigator Amanda Castel, MD, MPH, from George Washington University in DC, told Medscape Medical News. "There is a definite and urgent need for a lot of education and social marketing if pre-exposure prophylaxis is going to be an effective HIV prevention intervention."

In the past 18 months, several studies have shown that the option is an effective method of reducing HIV incidence in a variety of populations, including men who have sex with men, heterosexuals, and serodiscordant couples, where one person is negative for HIV and the other is positive.

Some ongoing trials are focusing on adolescents and young adults, but not many are looking at whether youth are even interested in pre-exposure prophylaxis or willing to take it, Dr. Castel said.

To find out, she and her colleagues surveyed 293 patients attending a clinic for sexually transmitted infections, a community-based general clinic for gay men, and a general adolescent health clinic at Children's National Medical Center in Washington, DC.

“The prevalence of HIV in Washington is higher than anywhere in Russia.”

All participants were HIV-negative and had had sex in the previous 6 months. Participants 13 to 24 years of age accounted for 45% of the cohort and those 25 years and older accounted for 55%.

"We were able to get waivers of parental consent so that we could include participants younger than 18," Dr. Castel noted.

The participants completed their surveys using iPads. "It takes away some of the interviewer bias because we were asking sensitive questions about sexual behaviors, condom use, that kind of thing," she said.

Just 31 participants had previously heard of pre-exposure prophylaxis, 9 of whom were in the younger age group.

Significantly more people in the older group than in the younger group reported that they were more likely to use the medication if it had few or no adverse effects (78% vs 62%; P = .02).

In addition, more older than younger participants reported that they would take medication if it were offered by their healthcare provider (70.6% vs 62.4%; P = .02) and would be able to follow a provider's instructions (76.9% vs 67.7%; P = .03).

Also, significantly more of the older group would prefer to take it after sex than as a daily medication (32% vs 20%; P = .004).

Finally, 64.7% of youth reported they would consider participating in future studies.

"Overall, there is very limited knowledge about pre-exposure prophylaxis and potentially poor adherence. Those things may pose pretty distinct barriers to implementation in this population," Dr. Castel said.

She conceded that taking medication every day for a condition that you don't have is difficult and requires strong motivation and organizational skills.

"A provider might have a patient who fits the high-risk-for-HIV profile, but that person might be terrible at adherence, so may not be a good candidate for pre-exposure prophylaxis, which requires taking it on a daily basis. In that situation, perhaps another prevention intervention, like encouraging condom use, could be tried," she said.

Injections of a long-acting antiretroviral might also be particularly useful for teens and young adults, she suggested.

Medscape Medical News asked Benjamin Young, MD, vice-president and chief medical officer of the International Association of Providers of AIDS Care in Washington, DC, to comment on the study. "This is a really interesting paper because we know from a number of large studies that pre-exposure prophylaxis can work in people who are at risk and who can be adherent to medication."

The study is particularly relevant in a place like Washington, DC, which has the highest prevalence of HIV in the United States, if not the world, Dr. Young added.

"I used to work part time in Russia, and the Russian Ministry of Health used to point out that the prevalence of HIV in Washington is higher than anywhere in Russia and approaches the prevalence in certain capital cities in East Africa. The United States takes on enormous efforts and spends all this money around the world, yet here in Washington, rates are super high, especially among young gay men and young gay men of color."

"I thought it was a travesty that Barrack Obama didn't walk the 3 or 4 blocks from the White House to the convention center during the AIDS conference last summer. It wasn't that he was tied up doing important state business or was out of the country. He was in the White House at the time and the flag was flying during the conference. That was particularly poignant if not outrageous to me, and I'm a supporter," Dr. Young said.

The failure on the part of President Obama to attend the AIDS conference highlights the problems that lead to such a high HIV prevalence in the nation's capital, he added.

"State-level programs work on prevention, but Washington, DC, because it doesn't have a state government but a somewhat dysfunctional city government and doesn't have adequate representation in congress, is forgotten," he said. "The AIDS epidemic is probably just one symptom of this. The study by Dr. Castel's team speaks to this problem. That is why it is important."

Dr. Young said he agrees that much more awareness about pre-exposure prophylaxis is needed.

"The amazing thing is that 90% of at-risk people didn't even know that it exists. It's probably the same nationwide; I don't think this is unique to Washington. But the study shows that people would use pre-exposure prophylaxis if they knew about it and could get it," he noted.

Dr. Castel reports no relevant financial relationships. Dr. Young is an employee of the International Association of Providers of AIDS Care and reports financial relationships with Bristol-Myers Squibb, GlaxoSmithKline, Merck & Co, ViiV Healthcare.

8th International Conference on HIV Treatment and Prevention Adherence. Presented June 3, 2013.

Source

HCV transmission rate higher among MSM with HIV

Provided by Healio
Witt M. Clin Infect Dis. 2013;57:77-84.

June 10, 2013

Transmission of hepatitis C virus among men who have sex with men has been occurring since early in the HIV epidemic, and the rates of infection are higher among those with HIV, according to data published in Clinical Infectious Diseases.

HCV transmission among MSM has been ongoing for at least 3 decades in both HIV-infected and HIV-uninfected men,” Chloe Thio, MD, associate professor of medicine at Johns Hopkins University, told Infectious Disease News. “Recent reports of HCV in MSM suggest that this is an emerging problem, so it was unexpected to find that transmission has been occurring at relatively high rates for several decades.”

From 1984 to 2011, the researchers prospectively followed 5,310 MSM who were enrolled in the Multicenter AIDS Cohort Study. The cohort included men with HIV and men at risk for HIV. All of the men tested negative for HCV antibody within 2 years of enrollment and at one or more follow-up visits through Sept. 30, 2011. Incident HCV infection was defined as a positive HCV antibody test at two or more follow-up visits.

The cohort was followed for a median of 7.1 years and had 55,343 person-years of follow-up. During this time, there were 115 incident HCV infections, with an incidence rate of 2.08 per 1,000 person-years (95% CI, 1.73-2.49). Among men with HIV, the incidence rate was 4.22, nearly 8.5-fold higher than the 0.5 incident rate for men without HIV.

In a multivariable analysis, factors associated with an increased risk for HCV included older age, HIV infection, being positive for hepatitis B surface antigen, history of injection drug use, drinking more than 13 drinks a week, syphilis and having unprotected receptive anal intercourse with multiple partners in the prior 6 months. Among men with HIV, the risk for HCV decreased as CD4+ counts increased from 0 cells/mm3 to 500 cells/mm3.

“These data emphasize the importance of checking for HCV in all MSM regardless of whether they are still sexually active, since they could have been infected decades ago,” Thio said. “In addition, counseling patients about the increased risk for receptive partners should also occur.”

Thio said that future research questions should address whether outcomes of the incident infections have changed over time. In addition, based on the finding that lower CD4+ counts are associated with increased risk for HCV, it is important to understand how immunosuppression from HIV affects acquisition of HCV.

For more information:

Chloe Thio, MD, can be reached at: Department of Medicine, Johns Hopkins University, 855 N. Wolfe St., Baltimore, MD, 21205.

Disclosure: Thio reports no relevant financial disclosures.

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Hepatitis B Viral Levels May Soar When Vitamin D Drops

Medscape Medical News

Diedtra Henderson

Jun 10, 2013

Insufficient serum levels of vitamin D, which ebb and flow with sun exposure, are associated with high levels of hepatitis B virus (HBV) replication in treatment-naive people who suffer from chronic infection.

Harald Farnik, from the Medizinische Klinik 1, Klinikum der Johann Wolfgang Goethe-Universität Frankfurt, Germany, and colleagues report the results of their study in an article published online May 22 in Hepatology.

HBV infection remains one of the most significant infectious diseases worldwide. According to the World Health Organization, 2 billion people worldwide have been infected with HBV, and roughly 600,000 die each year. Without antiviral therapy, the virus can attack the liver, and chronic infections progress to liver disease and cirrhosis. An emerging body of evidence has shown that vitamin D plays a role in inflammatory and metabolic liver diseases and that vitamin D can have a therapeutic effect for patients with tuberculosis. Although previous research has failed to demonstrate a correlation between hepatitis C viral load and circulating vitamin D levels, Dr. Farnik and colleagues sought to characterize the relationship between vitamin D metabolism and chronic hepatitis B.

They analyzed serum samples from treatment-naive patients with chronic hepatitis who visited the outpatient liver clinic of the Johann Wolfgang Goethe University Hospital in Frankfurt, Germany from January 2009 to December 2012. Two hundred and three patients were enrolled in the study. Every 3 HBV-infected patients enrolled in the study were randomly matched, according to age and sex, with 2 HCV-infected patients. Sixty-nine of the patients had severe vitamin D deficiency (25(OH)D3 levels < 10 ng/mL), 95 had vitamin D insufficiency (25(OH)D3 ≥ 10 ng/mL and < 20 ng/mL), and 39 had normal vitamin D levels (25(OH)D3 ≥ 20 ng/mL), Dr. Farnik and colleagues write.

"25(OH)D3 and HBV DNA serum levels showed a significant, inverse correlation (P=0.0003)," the authors write. "In both uni- and multivariate analyses, HBV DNA was the strongest determinant of low 25(OH)D3 serum concentration in our cohort (P=0.0007 and P=0.000048), respectively.

Additional studies will be needed to establish a causal relationship between vitamin D metabolism and HBV replication, the researchers write, as well as to explore the effect of adding supplemental vitamin D to existing therapies to improve the durability of treatment.

"In conclusion, we demonstrate a significant association between low 25(OH)D3 serum levels and high levels of HBV replication in chronically infected patients," they authors write. "Future studies to evaluate a therapeutic value of vitamin D and its analogs in HBV infection may be justified."

The authors have disclosed no relevant financial relationships.

Hepatology. Published online May 22, 2013. Abstract

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New Loyola Study on Hepatitis C Virus Entry Factor

Public release date: 10-Jun-2013
Contact: Stasia Thompson
thoms@lumc.edu
708-417-5036
Loyola University Health System

Loyola researchers identify disruption of iron uptake receptor

Hepatitis C virus (HCV) infects more than 170 million people worldwide. Approximately 80 percent of infections lead to chronic illness including fibrosis, cirrhosis, cancer and also hepatic iron overload. A new study completed by researchers at Loyola University Chicago Stritch School of Medicine reveals that HCV not only alters expression of the iron-uptake receptor known as transferrin receptor 1 (TfR1) but that TfR1 also mediates HCV entry.

"We have not yet discovered a cure for Hepatitis C, however discovering the relationship between HCV and TfR1 sheds more light on the complex, multistep process required for the virus to get into liver cells," said senior author Susan L. Uprichard, PhD, virologist and Director of Hepatology Research, Loyola. "This new knowledge reveals important insight into how the virus interacts with and changes our liver cells for its own benefit. As such, it may facilitate the development of entry inhibitors or treatments for HCV-associated iron overload." The research findings could also potentially be used in the clinical setting for the care of patients not only for those with chronic liver disease but also for post liver transplant where it might help prevent infection of a new liver or at least slow disease progression. Uprichard says her HCV research lays important groundwork. "This research is like finding one of the four corners of a puzzle," she said. "It creates a key building block toward finding a medical solution to Hepatitis C."

The new study is part of a project initially directed at understanding how HCV may disrupt cellular iron homeostasis. "TfR1 plays a role in HCV infection at the level of glycoprotein-mediated entry, acts after CD81 and is possibly involved in HCV particle internalization," said Danyelle Martin, the first author of the study who performed this research as part of her Ph.D work at University of Illinois at Chicago (UIC) and is now manager of the newly established Clinical Research Office Biobank at Loyola University Medical Center. "More studies will need to be done to determine if and how the interaction between TfR1 and HCV leads to the hepatic iron overload seen in HCV infected patients."

Results of the HCV study are published in the Proceedings of the National Academy of Sciences (PNAS) the week of June 10, 2013.

"The Hepatitis C Virus is fascinating and complex; we are still learning about the biology of the virus including the liver cell factors the virus needs to replicate and how these interactions cause the specific liver dysfunction observed in patients," said Uprichard, who also began the research while at UIC.

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Uprichard and Martin are members of the Division of Hepatology at Loyola University headed by Scott Cotler, MD and the Clinical Research Office led by Thomas Layden, MD.

Together with Harel Dahari, Ph.D, a mathematical modeler and another member of the Division of Hepatology, Dr. Uprichard co-directs a new Program for Experimental and Translational Modeling currently being established at Loyola to promote interdisciplinary research.

Source

Gilead's drug will be the first to hit the market in a new generation of targeted hepatitis C treatments with high cure rates.

By Jonathan Weiss, Ph.D. | Jun 10, 2013 10:05 AM EDT

Following successful late stage Phase III clinical trials of sofosbuvir, the FDA has granted a priority review designation for Gilead's new hepatitis C drug. If successful during the abbreviated approval process, Gilead expects the drug to be approved by December 8 of this year, making it one of the first in a new generation of drugs that target the virus itself to hit the market.

Sofosbuvir is a small molecule pharmaceutical compound, which acts on the hepatitis C polymerase and blocks the virus' ability to replicate its RNA.  The drug is meant to be used in combination with pegylated interferon (a longer lasting version of interferon alpha) and ribavirin (an antiviral currently used to treat hepatitis C). The drug can also be used with ribavirin alone or with other direct-acting antiviral (DAA) treatments.

Clinical trials from the drug showed great promise in curing patients of hepatitis C infection. A study published recently in the New England Journal of Medicine that we have previously covered showed that when combined with another antiviral drug, ribavirin, sofosbuvir was able to give a patient response rate of 93 percent for subtype 2, and 61 percent for subtype 3 of the hepatitis C virus. These two subtypes make up 25 percent of all hepatitis C cases in the United States. There are approximately four million Americans living with hepatitis C infections, many of whom are unaware of their infections.

Another clinical study called ELECTRON showed that interferon-free treatment with the drug and ribavirin caused a 100 percent response rate at 24 weeks post-treatment.  The study was conducted in patients who had hepatitis C with genotypes 2 and 3.

The oral pill will be prescribed for those with genotype 2 and 3 of the virus in combination with ribavirin. In patients who have never received treatment for hepatitis C, or naïve patients, and have genotypes 1, 4, 5 and 6, the oral drug would be used in combination with peg-interferon and ribavirin.

Hepatitis C treatments are coming out of the woodworks with almost every major pharmaceutical and biotechnology company set to be submitting drugs for approval within the next year. This comes as good news to those suffering from chronic hepatitis C virus infection. The virus can slowly cause liver failure because of scarring and can also result in liver cirrhosis. An estimated 130 to 200 million people worldwide are infected with the hepatitis C virus. Of people initially infected with the virus, 85 percent have the virus persist chronically.

The majority of liver transplants are performed because of hepatitis C infection. And sadly, even with a transplant, the virus can reassert itself. Currently, there is no vaccine for the virus.

Another drug, simeprevir, made by Medivir and Janssen, a division of Johnson & Johnson, was submitted last month to the FDA and also had promising late stage Phase III clinical trial results. Simeprevir targets a different pathway in the virus life cycle than Gilead's sofosbuvir does.

Source

Ending Mother-to-Child HIV Transmission

Huffington Post

Deborah Dugan CEO, (RED)

Posted: 06/10/2013 10:02 am

Imagine a world where no mother living with HIV will have to transmit the virus to her baby while giving birth. Just 10 years ago, this would have been considered an impossible goal. But, thankfully, with the incredible advances in HIV/AIDS treatment, prevention of mother-to-child transmission is real today and is helping the world take giant steps towards achieving an AIDS Free Generation. But still, 900 babies are born every day with HIV.

(RED) and the Global Fund envision a world in which no baby is born with HIV, and every mother has the opportunity to help her child thrive. To achieve this, ending mother-to-child transmission has become a cornerstone of (RED)'s commitment to the fight. But there is so much more to do before we get to our target, and we need the world to rally around making this a reality.

As a mother of three and CEO of (RED), the focus on safeguarding mothers and their babies from HIV couldn't hit closer to home. Our mission is to bring people and companies into the fight, to generate heat around the crisis and, through the Global Fund, enable some of the world's best-known companies to fund HIV/AIDS programs on the ground in Africa. Thanks to the incredible support of our partners (including Apple, Starbucks, Coca Cola and Belvedere), I am thrilled to announce that we have expanded our number of recipient countries to include Tanzania and Kenya - two countries with a high HIV/AIDS prevalence in which Global Fund programs funded by (RED) can make a real impact.

But real impact requires action. And money. Starting today, a new partnership with Johnson & Johnson means every time someone 'Likes', 'Tweets' or 'Pins' a (RED) infographic, Johnson & Johnson will donate $1 to the Global Fund, up to $100,000. Every cent from that donation will help ensure that HIV+ mothers in Africa have the tools they need to deliver healthy babies.

We are at a crucial point in the fight against HIV/AIDS. By acting now, and by acting collectively, our chances of helping deliver an AIDS Free Generation are infinitely greater.

This blog post was produced by The Huffington Post and (RED) as part of a series to support the CHOOSE (RED), SAVE LIVES campaign this June. To see other posts in the series and to see content from "The Big Push" (the initiative by the Global Fund, the recipient of (RED) monies, to fight AIDS, Tuberculosis and Malaria), click here. For more information about how you can join the fight against AIDS, please go to www.joinred.com/CHOOSERED.

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Huffington Post

C. Virginia Fields President & CEO, National Black Leadership Commission on AIDS

Posted: 06/10/2013 2:36 pm

I talk and write a lot about the disproportionate impact of HIV/AIDS and other health disparities on communities of color and other vulnerable populations. During Hepatitis C Awareness Month this past May, the National Black Leadership Commission on AIDS, Inc. (NBLCA) joined with other groups and organizations to educate and inform our communities about this often-invisible virus that has become a silent epidemic in the United States.

Left untreated, the Hepatitis C virus (HCV) causes potentially life-threatening liver damage. African Americans are twice as likely to be infected with HCV than non-Hispanic whites and are also twice as likely to have chronic (lifelong) rather than acute (non-recurring) Hepatitis C. Four times as many African Americans and Latinos have Hepatitis C than have HIV.

At highest risk for HCV infection are baby boomers -- people born between 1945 and 1964. According to the U.S. Centers for Disease Control and Prevention (CDC), more than 75 percent of the 3.2 million adults with HCV in the U.S. are baby boomers. Most don't even know they are infected, and without treatment, their risk of developing serious and even fatal liver diseases, such as cirrhosis and liver cancer, greatly increases.

On the June 5 premiere of Health Action Radio, the weekly, hour-long radio series presented by NBLCA on WWRL1600 AM in New York City, I moderated a discussion about Hepatitis C with Gloria Searson, president and founder of the Coalition on Positive Health Empowerment (COPE), and Hadiyah Charles, Hepatitis C Advocacy Manager at the Harm Reduction Coalition.

According to Ms. Searson, the majority of available information indicates that the lifestyles lived by many people in the 1970s, many of them baby boomers, exposed them in large numbers to the blood-borne Hepatitis C virus. (Many people were also infected during medical procedures before 1992, when the U.S. introduced universal blood product screening.) In fact, Ms. Searson indicated that many baby boomers have been living unknowingly with the virus for as long as 30 years. This is so because there are often no telltale signs of infection. She said baby boomers should be tested and screened not only for HCV but also for all seven types of hepatitis that exist.

Ms. Searson also noted that the co-infection rates for Hepatitis C and other diseases in communities of color are high. African Americans often fall through the cracks of the health care system because many access medical care only through emergency room visits. And, because instances of Hepatitis C are now based mostly on self-reporting, detection is difficult.

There are currently two ways to get tested: Ask for a blood test from your physician or go to an organization such as COPE for a rapid finger stick test, and within 20 minutes you will receive the results. If you don't have the virus, you will receive counseling and information that will help you prevent future infection. If you do test positive, you will be referred to appropriate and affordable care and treatment.

HCV is an epidemic and silent killer in the U.S. today, and we must be proactive about measures that will prevent its spread and help those at risk gain access to treatment. NBLCA fully supports New York State legislation A1286/S2750, which would require health care providers and hospitals to offer those born between 1945 and 1964, with their consent, screening for the Hepatitis C virus (HCV).

As Ms. Charles of the Harm Reduction Coalition pointed out, this legislation, if passed, may be a first-in-the-nation law that could be the "first domino" to fall that will prompt other states with a high HCV prevalence to follow suit.

Policy prompts action and influences budgets. It is imperative to get this legislation passed and signed into law. Since our legislators are working on behalf of us, their constituents, we want them to know that we support this ground-breaking, farsighted proposed legislation.

Please take action and call your state senator to encourage him or her to support A1286/S2750. There is information on the Harm Reduction Coalition's website to assist you in contacting your representatives. You can also help us show our state legislators that we have mobilized broad support for the measure by attending a rally in Albany on Tuesday, June 11.

Advocates, academics, medical professionals, legislators, policy experts, citizens, non-profit organizations, faith-based institutions, and others must work together to highlight and remedy the dire health consequences of Hepatitis C in our communities. We must have, as President Barack Obama has said so many times, all hands on deck.

Source

Sixty Percent of Surveyed Physicians Agree That They Are Beginning To Warehouse HCV Patients Until New Interferon-Free Regimens Are Available, According to a Recently Published BioTrends Report

May 23, 2013 - Exton, Penn. – BioTrends Research Group, one of the world’s leading research and advisory firms for specialized biopharmaceutical issues, finds that, unaided, one in five surveyed gastroenterologists, hepatologists, and infectious disease specialists reported that in the past six months, they have begun warehousing patients (e.g., intentionally delaying treatment) in anticipation of the next generation of HCV treatments—notably more physicians than six months ago, when only 6 percent reported that they had begun warehousing patients.

Furthermore, only one in five physicians agrees that they are satisfied with currently available treatment options, underscoring the high unmet need for alternatives to treat chronic HCV infections. The trending analyses of physician-reported anticipated prescribing in TreatmentTrends®: Hepatitis C Virus (US), Wave 1 also finds that, for the first time in a year, surveyed physicians are expecting to treat a greater proportion of their genotype 1 (3 percent) and 2/3 (3 percent) patients in the next six months with regimens that are not currently available. Unaided responses from most physicians who expect to be using other treatments suggest they are expecting products in development, potentially interferon-free regimens, to be available for use in the next six months.

In aided physician responses, Gilead’s sofosbuvir and Janssen/Medivir’s simeprevir garnered the highest degree of familiarity for use in HCV treatment, followed closely by Bristol-Myers Squibb’s daclatasvir and asunaprevir. Additionally, 20 percent of the surveyed physicians believe that Gilead’s sofosbuvir is the most promising product in development, primarily due to its favorable tolerability, oral dosing, pan-genotypic activity, and its possibility to be utilized as an interferon-free regimen.

“The protease inhibitors, Vertex’s Incivek and Merck’s Victrelis, were very important advances in the management of HCV infections,” said BioTrends Research Group Associate Director, Lynn Price. “However, there is still a clear unmet need for alternative HCV therapies and the recent NDA filings for simeprevir and sofosbuvir have physicians hopeful for new treatment options that are highly efficacious and more tolerable than the currently available protease inhibitors.”

TreatmentTrends®: Hepatitis C Virus (US), Wave 1 is a report that covers the use of agents for the treatment of HCV infections. This bi-annual study focuses on current and future use of leading HCV treatment regimens, patient market share, perceived strengths and weaknesses of the key brands, barriers to broader usage, sales force performance, and perceived value of manufacturers’ patient assistance programs. In addition, this report assesses potential impact of regimens in development, including Abbott’s ABT-267, ABT-333, and ABT-450, Boehringer Ingelheim’s BI-207127 and faldaprevir, Bristol-Myers Squibb’s asunaprevir and daclatasvir, Janssen’s simeprevir, and Gilead’s sofosbuvir and ledipasvir. In the current wave of research, BioTrends surveyed 101 U.S. gastroenterologists, hepatologists, and infectious disease specialists in March 2013.


About BioTrends Research Group
BioTrends Research Group provides syndicated and custom primary market research to pharmaceutical manufacturers competing in clinically evolving, specialty pharmaceutical markets. For information on BioTrends publications and research capabilities, please contact us at (610) 321-9400 or www. Bio-Trends. com. BioTrends is a Decision Resources Group company.

About Decision Resources Group
Decision Resources Group is a cohesive portfolio of companies that offers best-in-class, high-value information and insights on important sectors of the healthcare industry. Clients rely on this analysis and data to make informed decisions. Please visit Decision Resources Group at www.DecisionResourcesGroup.com.

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All company, brand, or product names contained in this document may be trademarks of their respective holders.


For more information, contact:

Lisa Osgood
Decision Resources Group
781-993-2606
losgood@dresourcesgroup.com

Source

Testing for HCV Infection

Morbidity & Mortality Weekly Report

Jane P. Getchell, DrPH, Kelly E. Wroblewski, MPH, Alfred DeMaria Jr, MD, Christine L. Bean, PhD, Monica M. Parker, PhD, Mark Pandori, PhD, D. Robert Dufour, MD, Michael P. Busch, MD, PhD, Mark E. Brecher, MD, William A. Meyer, PhD, Rick L. Pesano, MD, PhD, Chong-Gee Teo, MD, PhD, Geoffrey A. Beckett, MPH, Aufra C. Araujo, PhD, Bernard M. Branson, MD, Jan Drobeniuc, MD, PhD, Rikita Hatia, MPH, Scott D. Holmberg, MD, MPH, Saleem Kamili, PhD, John W. Ward, MD

Morbidity & Mortality Weekly Report. 2013;62(18):362-365.

Introduction

In the United States, an estimated 4.1 million persons have been infected with hepatitis C virus (HCV), of whom an estimated 3.2 (95% confidence interval [CI] = 2.7–3.9) million are living with the infection.[1] New infections continue to be reported particularly among persons who inject drugs and persons exposed to HCV-contaminated blood in health-care settings with inadequate infection control.[2]

Since 1998, CDC has recommended HCV testing for persons with risks for HCV infection.[3] In 2003, CDC published guidelines for the laboratory testing and result reporting of antibody to HCV.[4] In 2012, CDC amended testing recommendations to include one-time HCV testing for all persons born during 1945–1965 regardless of other risk factors.[1]

CDC is issuing this update in guidance because of 1) changes in the availability of certain commercial HCV antibody tests, 2) evidence that many persons who are identified as reactive by an HCV antibody test might not subsequently be evaluated to determine if they have current HCV,[5] and 3) significant advances in the development of antiviral agents with improved efficacy against HCV.[6] Although previous guidance has focused on strategies to detect and confirm HCV antibody,[3,4] reactive results from HCV antibody testing cannot distinguish between persons whose past HCV infection has resolved and those who are currently HCV infected. Persons with current infection who are not identified as currently infected will not receive appropriate preventive services, clinical evaluation, and medical treatment. Testing strategies must ensure the identification of those persons with current HCV infection.

This guidance was written by a workgroup convened by CDC and the Association of Public Health Laboratories (APHL), comprising experts from CDC, APHL, state and local public health departments, and academic and independent diagnostic testing laboratories, in consultation with experts from the Veterans Health Administration and the Food and Drug Administration (FDA). The workgroup reviewed laboratory capacities and practices relating to HCV testing, data presented at the CDC 2011 symposium on identification, screening and surveillance of HCV infection,[7] and data from published scientific literature on HCV testing. Unpublished data from the American Red Cross on validation of HCV antibody testing also were reviewed.

Changes in HCV Testing Technologies

Since the 2003 guidance was published,[4] there have been two developments with important implications for HCV testing:

  1. Availability of a rapid test for HCV antibody. The OraQuick HCV Rapid Antibody Test (OraSure Technologies) is a rapid assay for the presumptive detection of HCV antibody in fingerstick capillary blood and venipuncture whole blood. Its sensitivity and specificity are similar to those of FDA–approved, laboratory-conducted HCV antibody assays.[8] In 2011, a Clinical Laboratory Improvements Amendments waiver was granted to the test by FDA. The waiver provides wider testing access to persons at risk for HCV infection, permitting use of the assay in nontraditional settings such as physician offices, hospital emergency departments, health department clinics, and other freestanding counseling and testing sites.

  2. Discontinuation of RIBA HCV. The Chiron RIBA HCV 3.0 Strip Immunoblot Assay (Novartis Vaccines and Diagnostics) that was recommended[4] for supplemental testing of blood samples after initial HCV antibody testing is no longer available. As a result, the only other FDA-approved supplemental tests for HCV infection are those that detect HCV viremia.

Identifying Current HCV Infections

In 2011, FDA approved boceprevir (Victrelis, Merck & Co.) and telaprevir (Incivek, Vertex Pharmaceuticals) for treatment of chronic hepatitis C genotype 1 infection, in combination with pegylated interferon and ribavirin, in adult patients with compensated liver disease. Boceprevir and telaprevir interfere directly with HCV replication. Persons who complete treatment using either of these drugs combined with pegylated interferon and ribavirin are more likely to clear virus (i.e., have virologic cure), compared to those given standard therapy based on pegylated interferon and ribavirin.[9] Viral clearance, when sustained, stops further spread of HCV and is associated with reduced risk for hepatocellular carcinoma[10] and all-cause mortality.[11] Other compounds under study in clinical trials hold promise for even more effective therapies.[6]

Because antiviral treatment is intended for persons with current HCV infection, these persons need to be distinguished from persons whose infection has resolved. HCV RNA in blood, by nucleic acid testing (NAT), is a marker for HCV viremia and is detected only in persons who are currently infected. Persons with reactive results after HCV antibody testing should be evaluated for the presence of HCV RNA in their blood.

Benefits of Testing for Current HCV Infection

Accurate testing to identify current infection is important to 1) help clinicians and other providers correctly identify persons infected with HCV, so that preventive services, care and treatment can be offered; 2) notify tested persons of their infection status, enabling them to make informed decisions about medical care and options for HCV treatment, take measures to limit HCV-associated disease progression (e.g., avoidance or reduction of alcohol intake, and vaccination against hepatitis A and B), and minimize risk for transmitting HCV to others; and 3) inform persons who are not currently infected of their status and the fact that they are not infectious.

Recommended Testing Sequence

The testing sequence in this guidance is intended for use by primary care and public health providers seeking to implement CDC recommendations for HCV testing.[1,3,4] In most cases, persons identified with HCV viremia have chronic HCV infection. This testing sequence is not intended for diagnosis of acute hepatitis C or clinical evaluation of persons receiving specialist medical care, for which specific guidance is available.[12]

Testing for HCV infection begins with either a rapid or a laboratory-conducted assay for HCV antibody in blood (Figure). A nonreactive HCV antibody result indicates no HCV antibody detected. A reactive result indicates one of the following: 1) current HCV infection, 2) past HCV infection that has resolved, or 3) false positivity. A reactive result should be followed by NAT for HCV RNA. If HCV RNA is detected, that indicates current HCV infection. If HCV RNA is not detected, that indicates either past, resolved HCV infection, or false HCV antibody positivity.

804472-fig1

Recommended testing sequence for identifying current hepatitis C virus (HCV) infection

* For persons who might have been exposed to HCV within the past 6 months, testing for HCV RNA or follow-up testing for HCV antibody is recommended. For persons who are immunocompromised, testing for HCV RNA can be considered.
To differentiate past, resolved HCV infection from biologic false positivity for HCV antibody, testing with another HCV antibody assay can be considered. Repeat HCV RNA testing if the person tested is suspected to have had HCV exposure within the past 6 months or has clinical evidence of HCV disease, or if there is concern regarding the handling or storage of the test specimen.

Initial Testing for HCV Antibody

An FDA-approved test for HCV antibody should be used. If the OraQuick HCV Rapid Antibody Test is used, the outcome is reported as reactive or nonreactive. If a laboratory-based assay is used, the outcome is reported as reactive or nonreactive without necessarily specifying signal-to-cutoff ratios.

Testing for HCV RNA

An FDA-approved NAT assay intended for detection of HCV RNA in serum or plasma from blood of at-risk patients who test reactive for HCV antibody should be used. There are several possible operational steps toward NAT after initial testing for HCV antibody:

  1. Blood from a subsequent venipuncture is submitted for HCV NAT if the blood sample collected is reactive for HCV antibody during initial testing.

  2. From a single venipuncture, two specimens are collected in separate tubes: one tube for initial HCV antibody testing; and a second tube for HCV NAT if the HCV antibody test is reactive.

  3. The same sample of venipuncture blood used for initial HCV antibody testing, if reactive, is reflexed to HCV NAT without another blood draw for NAT.[13]

  4. A separate venipuncture blood sample is submitted for HCV NAT if the OraQuick HCV Rapid Antibody Test for initial testing of HCV antibody has used fingerstick blood.

Supplemental Testing for HCV Antibody

If testing is desired to distinguish between true positivity and biologic false positivity for HCV antibody, then, testing may be done with a second HCV antibody assay approved by FDA for diagnosis of HCV infection that is different from the assay used for initial antibody testing. HCV antibody assays vary according to their antigens, test platforms, and performance characteristics, so biologic false positivity is unlikely to be exhibited by more than one test when multiple tests are used on a single specimen.[14]

Test Interpretation and Further Action

Table.  Interpretation of results of tests for hepatitis C virus (HCV) infection and further actions

Test outcome Interpretation Further action
HCV antibody nonreactive No HCV antibody detected Sample can be reported as nonreactive for HCV antibody. No further action required.

If recent HCV exposure in person tested is suspected, test for HCV RNA.*
HCV antibody reactive Presumptive HCV infection A repeatedly reactive result is consistent with current HCV infection, or past HCV infection that has resolved, or biologic false positivity for HCV antibody. Test for HCV RNA to identify current infection.
HCV antibody reactive,

HCV RNA detected
Current HCV infection Provide person tested with appropriate counseling and link person tested to medical care and treatment.
HCV antibody reactive,

HCV RNA not detected
No current HCV infection No further action required in most cases.

If distinction between true positivity and biologic false positivity for HCV antibody is desired, and if sample is repeatedly reactive in the initial test, test with another HCV antibody assay.

In certain situations
§ follow up with HCV RNA testing and appropriate counseling.

* If HCV RNA testing is not feasible and person tested is not immunocompromised, do follow-up testing for HCV antibody to demonstrate seroconversion. If the person tested is immunocompromised, consider testing for HCV RNA.
It is recommended before initiating antiviral therapy to retest for HCV RNA in a subsequent blood sample to confirm HCV RNA positivity.
§If the person tested is suspected of having HCV exposure within the past 6 months, or has clinical evidence of HCV disease, or if there is concern regarding the handling or storage of the test specimen.

Laboratory Reporting

"Acute hepatitis C" and "hepatitis C (past or present)" are nationally notifiable conditions, and are subject to mandated reporting to health departments by clinicians and laboratorians, as determined by local, state or territorial law and regulation. Surveillance case definitions are developed by the Council of State and Territorial Epidemiologists in collaboration with CDC.[15] In all but a few jurisdictions, positive results from HCV antibody and HCV RNA testing that are indicative of acute, or past or present HCV infection, are reportable. Specific policies for laboratory reporting are found at health department websites.[16]

Future Studies

Research, development, validation, and cost-effectiveness studies are ongoing to inform the best practices for detecting HCV viremia and for distinguishing between resolved HCV infection and biologic false positivity for HCV antibody in persons in whom HCV RNA is not detected. Outcomes of these studies will provide comprehensive guidance on testing, reporting, and clinical management, and will improve case definitions for disease notification and surveillance.

References
  1. CDC. Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945–1965. MMWR 2012;61(No. RR-4).

  2. CDC. Viral hepatitis surveillance, United States, 2009–2011. Atlanta, GA: US Department of Health and Human Services, CDC; 2012. Available at http://www.cdc.gov/hepatitis/statistics/2010surveillance/index.htm.

  3. CDC. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. MMWR 1998;47(No. RR–19).

  4. CDC. Guidelines for laboratory testing and result reporting of antibody to hepatitis C virus. MMWR 2003;52(No. RR–3).

  5. CDC. Vital signs: evaluation of hepatitis C virus infection testing and reporting—eight U.S. sites, 2005–2011. MMWR 2013;62(18).

  6. Poordad F, Dieterich D. Treating hepatitis C: current standard of care and emerging direct-acting antiviral agents. J Viral Hepat 2012;19:449–64.

  7. CDC. Viral Hepatitis Resource Center: 2011 HCV Symposium. Atlanta, GA: US Department of Health and Human Services, CDC; 2011. Available at http://www.cdc.gov/hepatitis/resources/mtgsconf/hcvsymposium2011.htm.

  8. Shivkumar S, Peeling R, Jafari Y, Joseph L, Pant Pai N. Accuracy of rapid and point-of-care screening tests for hepatitis C: a systematic review and meta-analysis. Ann Intern Med 2012;157:558–66.

  9. Cooper C, Lester R, Thorlund K, et al. Direct-acting antiviral therapies for hepatitis C genotype 1 infection: a multiple treatment comparison meta-analysis. QJM 2013;106:153–63.

  10. Morgan RL, Baack B, Smith BD, Yartel A, Pitasi M, Falck-Ytter Y. Eradication of hepatitis C virus infection and the development of hepatocellular carcinoma. A meta-analysis of observational studies. Ann Intern Med 2013;158:329–37.

  11. Backus LI, Boothroyd DB, Phillips BR, Belperio P, Halloran J, Mole LA. A sustained virologic response reduces risk of all-cause mortality in patients with hepatitis C. Clin Gastroenterol Hepatol 2011;9:509–16.

  12. Ghany MG, Strader DB, Thomas DL, Seeff LB; American Association for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology 2009;49:1335–74.

  13. Gale HB, Dufour DR, Qazi NN, Kan VL. Comparison of serial hepatitis C virus detection in samples submitted through serology for reflex confirmation versus samples directly submitted for quantitation. J Clin Microbiol 2011;49:3036–9.

  14. Vermeersch P, Van Ranst M, Lagrou K. Validation of a strategy for HCV antibody testing with two enzyme immunoassays in a routine clinical laboratory. J Clin Virol 2008;42:394–8.

  15. CDC. MMWR: Public health resources—state health departments. Atlanta, GA: US Department of Health and Human Services, CDC; 2011. Available at: http://www.cdc.gov/mmwr/international/relres.html.

  16. CDC. 2013 National notifiable infectious conditions. Atlanta, GA: US Department of Health and Human Services, CDC; 2012. Available at http://wwwn.cdc.gov/nndss/script/conditionlist.aspx?type=0&yr=2013.

Morbidity & Mortality Weekly Report. 2013;62(18):362-365. © 2013 Centers for Disease Control and Prevention (CDC)

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PR-Logo-Newswire

PRESS RELEASE

June 10, 2013, 9:30 a.m. EDT

NEW YORK, June 10, 2013 /PRNewswire via COMTEX/ -- The National Black Leadership Commission on AIDS, Inc. (NBLCA) is working in partnership with allied organizations to advocate for the passage of New York State Senate (S2750) and Assembly (A1286) bills to expand access to testing for the Hepatitis C virus (HCV), which has reached epidemic proportions in New York and the United States. The proposed legislation would require hospitals and health care practitioners to offer Hepatitis C screenings to all people born between 1945 and 1964--the "Baby Boomer" generation, which has been disproportionately affected by HCV. Advocates are organizing a rally in Albany on Tuesday, June 11, to urge passage of the bill.

According to the U.S. Centers for Disease Control and Prevention (CDC), more than 75 percent of the 3.2 million adults with HCV in the United States are Baby Boomers. Because there are often no noticeable symptoms, most of them don't know they are infected with the virus, and without treatment, they face a greatly increased risk of developing potentially life-threatening liver diseases, such as cirrhosis and liver cancer.

In New York State, Boomers have the highest HCV infection rate of any group. The NYS Department of Health estimates that more than 200,000 New Yorkers have the virus--60 percent of them in New York City--but 75 percent of them don't know their status. African Americans are two times as likely as non-Hispanic white people to be infected and are less likely to be tested and to receive treatment.

The Hepatitis C virus is transmitted by blood-to-blood contact. Since no vaccine for HCV is available, testing is crucial to prevent new infections. "By getting tested and determining their status, those at risk can get life-saving treatment and learn how to protect themselves against future infection," said NBLCA President and CEO C. Virginia Fields. "We need to educate and inform as many people as possible about this often invisible virus that has become a silent epidemic in the United States. We urge New Yorkers to contact their local and state elected officials to support passage of this critical state legislation that will expand access to testing and set an example for other communities throughout the nation."

For information about the June 11 Albany rally, call 212-614-0023 or email rarichards@nblca.org. For more about HCV or the proposed legislation, visit www.nblca.org and listen to the premiere of Health Action Radio, hosted by NBLCA on WWRL-AM 1600, featuring C. Virginia Fields and experts on medical issues and policies related to HCV.

Media Contact:

Teri Wade, 212-595-4047, teri@missionandmessage.com 

SOURCE National Black Leadership Commission on AIDS, Inc.

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Partial Livers from Deceased Donors Saving the Lives of Infants

Press Release

June 10, 2013

New research reveals that transplantation of partial livers from deceased adult and teen donors has become less risky for infants and young children, helping to save these young lives. Findings published online in Liver Transplantation, a journal of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society, indicate that risk of organ failure and mortality from partial or split liver transplant was comparable to whole organ transplant in this pediatric population.

Available livers for transplantation are in short supply, particularly size-matched organs for the youngest patient on the waitlist. While there is evidence that partial organs donated from living donors are superior to those from deceased donors, they accounted for less than 11% of pediatric liver transplants in 2010. Since 2002, studies show an eight-fold increase in the use of partial grafts from deceased donors, accounting for up to 32% of liver transplants in children.

“Infants and young children have the highest waitlist mortality rates among all candidates for liver transplant,” explains senior author Dr. Heung Bae Kim, Director of the Pediatric Transplant Center at Boston Children’s Hospital in Massachusetts. “Extended time on the liver transplant waitlist also places children at greater risk for long-term health issues and growth delays, which is why it is so important to look for methods that shorten the waitlist time to reduce mortality and improve quality of life for pediatric patients.”

To further understand outcomes of using deceased donor partial livers in infants, the team identified 2,679 liver transplant recipients under the age of two in the United Network of Organ Sharing (UNOS) database from 1995-2010. There were 1,114 partial livers and 1,565 whole organs from deceased donors that were used in the transplants analyzed. They examined mortality and graft survival over time.

Graft survival between partial and whole grafts were significantly different in 1995-2000, but comparable in 2001-2005 and 2006-2010, suggesting that transplants using partial livers became less risky over time. Adjusted risk of graft failure and mortality was similar for partial and whole organs in 2006-2010.

“Infants continue to have twice the mortality rate of adult candidates on the waitlist,” concludes Dr. Kim. “Our study confirms that organ failure and mortality risk in the very young was similar for partial and whole organs from deceased donors. The transplant community must continue to look for ways to reduce mortality rates in pediatric patients and using partial livers from deceased, as well as living donors, may hold the key.”

Full citation: “Deceased Donor Liver Transplantation in Infants and Small Children: Are Partial Grafts Riskier Than Whole Organs?” Ryan P. Cauley, Khashayar Vakili, Kristina Potanos, Nora Fullington, Dionne A. Graham, Jonathan A. Finkelstein and Heung Bae Kim. Liver Transplantation; (DOI: 10.1002/lt.23667) Online Publication: May 21, 2013.
URL:
http://doi.wiley.com/10.1022/lt.23667

Source

Published: June 10, 2013

- BL-8030 is a pre-clinical, second-generation NS3 protease inhibitor -- CTTQ receives development and commercialization rights in China and Hong Kong -

JERUSALEM — BioLineRx (NASDAQ: BLRX) (TASE: BLRX), a biopharmaceutical development company, announced today that it has signed an out-licensing agreement with Jiangsu Chia-tai Tianqing Pharmaceutical Co., Ltd. (CTTQ), the leading Chinese pharmaceutical company in the liver disease therapeutic area, for the development and commercialization of BL-8030, an orally available treatment for the Hepatitis C virus (HCV).

Under the terms of the agreement, BioLineRx will grant CTTQ exclusive rights to develop, manufacture and commercialize BL-8030 in China and Hong Kong. CTTQ will pay BioLineRx an upfront license fee, plus future development, regulatory and commercialization milestones, for a total potential deal value of approximately $30 million. In addition, BioLineRx has the right to receive high single-digit royalties on future sales of the drug. BioLineRx will retain the right to develop and commercialize BL-8030 in other parts of the world. CTTQ will adhere to FDA and EMA guidelines in pre-clinical development and manufacturing of BL-8030. BioLineRx will have access to all development and regulatory data generated by CTTQ, as well as the right to use this data for commercialization and regulatory purposes in all areas of the world outside of China and Hong Kong.

“We look forward to developing and commercializing BL-8030 with CTTQ, the leading pharmaceutical company in China in the field of liver diseases,” said Kinneret Savitsky, Ph.D., Chief Executive Officer of BioLineRx. "We are proud that since in-licensing this promising pre-clinical asset just over one year ago, we have found a strong partner for the further development of BL-8030 in China, which is a significant market in the HCV field. We believe that given CTTQ's extensive experience in the liver disease area, it will swiftly advance the development of BL-8030 at the highest global standards. In parallel to collaborating with CTTQ to advance the drug, we intend to continue discussions with relevant partners for this project in other parts of the world.”

"We are excited to include BL-8030 as a new asset in our pipeline," said Mr. Jian Sun Emba, President of CTTQ. "Unfortunately, the prevalence of HCV is relatively significant in China, with reports of 3.2% of the population (amounting to approximately 43 million individuals) suffering from this chronic and debilitating disease. Thus there is a clear and urgent need to develop new, safe and effective treatments for HCV patients in China. After conducting a thorough due diligence process, we sincerely believe that BL-8030, even though still in pre-clinical development, has the potential to become an important addition to HCV combination therapies."

Professor Philippe Halfon, world-renowned scientist for his work on HIV, HPV (human papilloma virus causing cervical cancer) and Hepatitis, and a co-inventor of BL-8030, said, "BL-8030 has shown promising results in pre-clinical studies, and may become an important part of combination therapies for HCV. Current treatments are only partially effective and adverse effects are common, so there is a clear need for new drugs that will be both safe and effective."

About BL-8030

BL-8030, an orally available treatment for Hepatitis C, is a potent and selective second generation NS3 protease inhibitor. The NS3 protease is essential for replication of the Hepatitis C virus and is an important target for HCV therapies. BL-8030 has been shown to have excellent antiviral activity, in the low nanomolar range, against a wide range of HCV genotypes. Pre-clinical studies have demonstrated an improved resistance profile against common protease inhibitor mutants, resulting in a lower probability that the virus will develop resistance to treatment. In addition, BL-8030 has demonstrated a good safety profile in pre-clinical studies, exhibiting specificity only to the viral protease and lack of activity against a relevant panel of human proteases, as well as a clean profile versus human liver enzymes, which is expected to lead to less drug-drug interactions. PK studies in animals indicated the BL-8030 has good oral bioavailability, suggesting the potential for once-daily dosing in the clinic.

In February 2012, BioLineRx signed a worldwide, exclusive license agreement with Genoscience and RFS Pharma, LLC to develop and commercialize BL-8030. BL-8030 was invented by Professor Philippe Halfon and his team at Genoscience, and co-developed with scientists at RFS Pharma, LLC. Prof. Halfon, Co-Founder and President of Genoscience, is a specialist in molecular virology and infectious diseases, especially HIV, HPV and Hepatitis. In addition he is the founder of several biotechnology companies focusing on antiviral drug discovery and development, including ACTgene, Alphabio and Genoscience. RFS Pharma was founded in 2004 by Professor Raymond Schinazi; he currently serves as the Frances Winship Walters Professor of Pediatrics at Emory University. He is also a principal founder of Pharmasset Inc., Idenix Inc. and Triangle Pharmaceuticals.

About Hepatitis C

Hepatitis C is a blood borne infection of the liver caused by the Hepatitis C virus which becomes chronic in about 85% of cases. According to the World Health Organization, up to 170 million people worldwide are chronically infected with HCV. In addition, HCV infection is the leading cause of liver transplantation and is a risk factor for liver cancer. The Hepatitis C market is growing rapidly and is forecasted to reach $16 billion in 2015 in the seven major markets (US, France, Germany, Italy, Spain, UK and Japan).

About CTTQ

Jiangsu Chia-tai Tianqing Pharmaceutical Co., Ltd. (CTTQ), headquartered in Nanjing and Lianyungang, Jiangsu Province, China, is a large pharmaceutical manufacturer, integrating research, production and sales. The company is one of the top 50 companies in China’s pharmaceutical industry. CTTQ’s products are in a wide array of therapeutic areas, including hepatitis, cancer, cardio-vascular, anti-virus, digestion, respiratory and diabetes, with a particular emphasis on liver diseases, where it is the leading Chinese company in that field. CTTQ is a subsidiary of Sino Biopharmaceutical Ltd., a publicly traded company on the Hong Kong Stock Exchange.

About BioLineRx

BioLineRx is a publicly-traded biopharmaceutical development company. BioLineRx is dedicated to building a portfolio of products for unmet medical needs or with advantages over currently available therapies. BioLineRx’s current portfolio consists of seven clinical stage candidates: BL-1040, for prevention of pathological cardiac remodeling following a myocardial infarction, which has been out-licensed to Ikaria Inc., is currently undergoing a pivotal CE-Mark registration trial; BL-5010 for non-surgical removal of skin lesions has completed a Phase 1/2 study; BL-7040 for treating inflammatory bowel disease (IBD) has successfully completed a Phase 2a trial; BL-8040 for treating acute myeloid leukemia (AML) and other hematological cancers has commenced a Phase 2 study; BL-1021 for neuropathic pain is in Phase 1 development; BL-8020 for hepatitis C (HCV) has commenced a Phase 1/2 study; and BL-1020 for schizophrenia. In addition, BioLineRx has five products in various pre-clinical development stages for a variety of indications, including central nervous system diseases, infectious diseases, cardiovascular and autoimmune diseases.

BioLineRx’s business model is based on acquiring molecules mainly from biotechnological incubators and academic institutions. The Company performs feasibility assessment studies and development through pre-clinical and clinical stages, with partial funding from the Israeli Government’s Office of the Chief Scientist (OCS). The final stage includes partnering with medium and large pharmaceutical companies for advanced clinical development and commercialization. For more information on BioLineRx, please visit www.biolinerx.com, the content of which does not form a part of this press release.

Various statements in this release concerning BioLineRx’s future expectations, including specifically those related to the development and commercialization of BL-8030, constitute “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. These statements include words such as “may,” “expects,” “anticipates,” “believes,” and “intends,” and describe opinions about future events. These forward-looking statements involve known and unknown risks and uncertainties that may cause the actual results, performance or achievements of BioLineRx to be materially different from any future results, performance or achievements expressed or implied by such forward-looking statements. Some of these risks are: changes in relationships with collaborators; the impact of competitive products and technological changes; risks relating to the development of new products; and the ability to implement technological improvements. These and other factors are more fully discussed in the “Risk Factors” section of BioLineRx’s most recent annual report on Form 20-F filed with the Securities and Exchange Commission on March 12, 2013. In addition, any forward-looking statements represent BioLineRx’s views only as of the date of this release and should not be relied upon as representing its views as of any subsequent date. BioLineRx does not assume any obligation to update any forward-looking statements unless required by law.

Source

Sorafenib: from literature to clinical practice

Ann Oncol (2013) 24 (suppl 2): ii30-ii37. doi: 10.1093/annonc/mdt055 This article appears in: Current issues in the management of hepatocellular carcinoma

V. Di Marco1,*, F. De Vita2, J. Koskinas3, D. Semela4, P. Toniutto5 and C. Verslype6

+ Author Affiliations

  1. 1Sezione di Gastroenterologia & Epatologia, Dipartimento Biomedico di Medicina Interna e Specialistica (Di.Bi.M.I.S.), University of Palermo, Palermo
  2. 2Oncologia Medica, Seconda Università di Napoli, Naples, Italy
  3. 3Department of Medicine, Medical School of Athens, Hippokration General Hospital, Athens, Greece
  4. 4Division of Gastroenterology and Hepatology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland
  5. 5Medical Liver Transplant Unit, Department of Medical Sciences Clinical and Experimental, University of Udine, Udine, Italy
  6. 6Hepatology, University Hospital Gasthuisberg, Leuven, Belgium
  7. *Correspondence to: Prof. Vito Di Marco, Sezione di Gastroenterologia & Epatologia, Dipartimento Biomedico di Medicina Interna e Specialistica (Di.Bi.M.I.S.), University of Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy. Tel: +39-091-6552106; Fax: +39-091-6552156; E-mail: vito.dimarco@unipa.it

Abstract

Sorafenib is considered the standard systemic therapy for hepatocellular carcinoma (HCC), in patients with well-preserved liver function (Child-Pugh A class) and advanced-stage HCC (BCLC-C) or in patients with HCC progressing after locoregional therapies, with a high grade of recommendation. The approval of sorafenib for this indication was grounded on the efficacy and the safety results reported by two international randomized, controlled trials, the SHARP and the Asia-Pacific studies. In addition, the efficacy and the safety of sorafenib in clinical practice are addressed by several field-practice experiences, including the multinational GIDEON study and the SOFIA study. Finally, further research on sorafenib is ongoing to optimize the use of this molecule. This review aims to provide an overview of the most relevant clinical data on the efficacy and the safety of sorafenib in patients with HCC.

Key words adverse events, clinical practice, observational studies, randomized clinical trials, sorafenib
introduction

Hepatocellular carcinoma (HCC) represents a global health problem and the incidence of this cancer in patients with cirrhosis is still increasing in several countries. The prognosis and the treatment options for HCC are generally related to the tumor stage at presentation. Surgical resection, transplantation and percutaneous ablation offer a high probability of complete response in patients with early HCC. In asymptomatic patients with multifocal HCC without vascular invasion or extrahepatic spread, chemoembolization can provide survival benefit.

Sorafenib, an oral multikinase inhibitor with activity against Raf-1, B-Raf, VEGFR2, PDGFR and c-Kit receptors, has a potent antiangiogenic and proapoptotic activity and therefore presents a marked antitumoral effect [1].

The improvement of survival in patients treated with sorafenib is supported by the highest level of evidence, and according to the recent guidelines by the European Association for the Study of Liver (EASL) and by the European Society for Molecular Oncology (ESMO)/European Society of Digestive Oncology (ESDO), sorafenib is considered the standard systemic therapy for HCC, in patients with well-preserved liver function (Child-Pugh A class) and advanced-stage HCC (BCLC-C) or in patients with HCC progressing after locoregional therapies, with a high grade of recommendation (Figure 1) [2,3].

F1_medium

Figure 1. Representation of the EASL recommendations for treatment according to levels of evidence. Reproduced with permission from European Association for the Study of the Liver, European Organisation for Research and Treatment of Cancer [2].

Sorafenib was approved for the treatment of patients with advanced HCC on the basis of the efficacy and the safety results reported by two international randomized, controlled trials (RCTs), the SHARP (Sorafenib HCC Assessment Randomized Protocol) and the Asia-Pacific trials [4,5]. In addition, the efficacy and the safety of sorafenib in clinical practice are addressed by several field-practice experiences, including the multinational GIDEON study and the SOFIA study [6,7]. Finally, further research on sorafenib is ongoing to optimize the use of this molecule, and particularly, the efficacy of sorafenib in patients with Child-Pugh B cirrhosis, the possibility of modifying the dosing regimen and the potential existence of laboratory and/or genetic biomarkers of response are currently being explored.

This review aims to provide an overview of the most relevant clinical data on the efficacy and the safety of sorafenib in patients with HCC.

randomized, controlled trials

efficacy

The SHARP trial, conducted in Western countries, was a multicenter, phase III, double-blind, placebo-controlled study, in which 602 HCC patients (95% with Child-Pugh A cirrhosis and 82% with BCLC-C) who had not received any previous systemic treatment were assigned to receive sorafenib 400 mg bis in die (bid) or placebo [4]. The primary outcomes of the trial were overall survival (OS) of patients and the time to symptomatic progression, whereas the secondary outcomes included the time to radiologic progression (TTP) and safety. The study was stopped at the second planned interim analysis, due to a significantly shorter survival in the placebo arm. In detail, the median OS was 10.7 months in the sorafenib group versus 7.9 months in the placebo group [hazard ratio (HR): 0.69; 95% CI: 0.55–0.87; P < 0.001]. Although there was no difference in the median time to symptomatic progression, a significant advantage for sorafenib over placebo was reported for TTP (5.5 versus 2.8 months; P < 0.001).

The second trial with a similar design was conducted in the Asia-Pacific region, where chronic infection by hepatitis B virus (HBV) represents the more common etiological factor of chronic liver disease [5]. In total, 226 patients with HCC were randomized to receive sorafenib 400 mg bid or placebo with a 2:1 ratio (150 and 76 patients, respectively). The wide majority of patients were classified as Child-Pugh A (97%) and BCLC-C (95%). The efficacy of sorafenib was overall similar to that reported in the SHARP trial. The median OS was 6.5 months in the sorafenib group, compared with 4.2 months in the placebo group, with an HR similar to that observed in the SHARP trial (HR: 0.68; 95% CI: 0.50–0.93; P = 0.014), whereas the median TTP was 2.8 months in the sorafenib group compared with 1.4 months in the placebo group (P = 0.0005).

It must be observed that the two trials have enrolled different populations: patients included in the SHARP trial were mostly of Caucasian ethnicity and had a high prevalence of hepatitis C virus infection; conversely, patients observed in the Asia-Pacific trial were more largely infected by HBV and presented a more advanced stage of HCC and a worse liver function. These differences can explain the difference in OS observed between the two trials; however, the HR for survival, which can be regarded to as a measure of sorafenib efficacy, was similar (0.69 and 0.68, respectively).

safety

In both the SHARP and the Asia-Pacific trials, sorafenib was generally well tolerated, but, like other drugs of the same class, it caused a range of adverse events (AEs). In the SHARP trial, the incidence of serious AEs was 52 and 54% in treated and placebo groups, respectively [4]. However, grade 3 drug-related AEs were more common in the sorafenib group and included diarrhea (8%), hand–foot skin reaction (HFSR) (8%), hypertension (2%) and abdominal pain (2%). The rate of patients who discontinued treatment was similar in the two groups (38 and 37%, respectively), but treatment was permanently discontinued due to toxicity in 11% of sorafenib-treated patients versus 5% of placebo patients. In the Asia-Pacific trial, the most frequent grade 3/4 drug-related AEs in the sorafenib group were HFSR (10.7%), diarrhea (6.0%) and fatigue (3.4%) [5]. The most common AEs resulting in dose reductions were HFSR (11.4%) and diarrhea (7.4%), but these AEs were overall manageable and rarely led to discontinuation of treatment.

clinical practice studies

RCTs provide the highest level of evidence for the rigorous design, the application of strict selection criteria for the inclusion of patients, and the precise evaluation of the efficacy and the safety in a well-defined population. However, patients enrolled in RCTs often do not closely represent the clinical practice, due to the necessary absence of potential confounding factors like concomitant diseases or other treatments [7,8]. Observational studies can complement findings from RCTs, as they assess treatment effectiveness in patients encountered in day-to-day clinical practice [8]. Therefore, results from well-designed observational studies can expand upon the outcomes of RCTs, thanks to the observation of the large cohort of patients who present co-morbidities and receive concomitant medications. Furthermore, observational studies can identify clinically important differences among therapeutic options and provide data on drug efficacy and safety over a longer-term follow-up than RCTs.

At present, the results of two real clinical experiences conducted on sorafenib are available: the GIDEON study (Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib), conducted on a very large population of HCC patients in more than 40 countries [6], and the SOFIA (SOraFenib Italian Assessment) study, conducted in Italy [7]. These two studies reported the clinical outcomes of patients on treatments and, particularly, addressed the management of sorafenib-related AEs in daily clinical practice.

the GIDEON study

The GIDEON study, still ongoing, is a global phase IV, international, prospective, open-label, multicentre, non-interventional post-marketing study of patients with advanced-stage HCC receiving sorafenib under real-life conditions [6]. A very large cohort of 3275 patients have been recruited from Europe, Latin America, the USA and the Asia-Pacific regions. The main goal of the study was to evaluate the safety and efficacy of sorafenib in different patient subgroups, especially in subjects with Child-Pugh B cirrhosis, where data were limited. Additional aims of this study were to compile a large database and to analyze potential local, regional and global differences in baseline characteristics, disease etiology, treatment, practice patterns and treatment outcomes. The study completion is expected by 2013.

The second preplanned interim analysis available has been presented at the Annual Congress of the American Association for the Study of Liver Diseases (AASLD) in November 2011 [9]. The interim analysis reported the efficacy and safety data of sorafenib in clinical practice in two subgroups of patients: a group who started the treatment with the standard dose of 800 mg/day and a group who started the treatment with 400 mg/day or other doses.

In total, 1571 patients had valid data for the safety evaluation and 1612 patients for the efficacy evaluation. At baseline, 61% of patients had a Child-Pugh A and 23% a Child-Pugh B cirrhosis, 54% of patients had a BCLC-C and 19% a BCLC-B, 40% of patients had a performance status (PS) 0 and 43% a PS 1 and 55% of patients received a previous locoregional treatment. In most cases (75%), patients initiated sorafenib at the recommended dose of 800 mg/day. The remaining patients received 400 mg/day (22%) or other dosages (3%). The two groups were comparable for the Child-Pugh score, BCLC stage, PS and rate of patients who received a previous surgery or locoregional treatment.

The interim analysis showed a trend toward more evident benefits for sorafenib at the recommended dose, when compared with the lower dose of 400 mg/day. In particular, patients who initiated sorafenib at the dose of 800 mg/day tended to stop treatment later than patients who started sorafenib with a dose of 400 mg/day (12.3 versus 9.7 weeks) and present a longer OS (9.3 versus 7.1 months) and TTP (4.5 versus 3.6 months) [9].

The most commonly reported AEs in both dose groups were diarrhea, HFSR and fatigue, and these AEs were in most cases mild (grade 1/2). No significant differences in the type and the incidence of AEs between the recommended dose group and the 400 mg/day dose group were reported [9]. This analysis suggests that initiating sorafenib treatment at the full recommended dose of 800 mg/day may be associated with some advantages in terms of duration of therapy, OS and TTP versus a 400 mg/day starting dose, without any relevant worsening of the safety profile of the molecule [9].

the SOFIA study

The SOFIA study was a smaller multicenter, investigator-driven, observational, non-interventional study conducted in six referral Italian centers with the aim to assess sorafenib safety in clinical practice and to evaluate treatment efficacy in terms of OS, early radiologic response and TTP [7]. In total, 296 consecutive patients (88% Child-Pugh A) with advanced-stage HCC (75%) or intermediate-stage HCC and/or not eligible to or who failed ablative therapies (25%) were enrolled. At the initiation of therapy, sorafenib was administered at dose of 800 mg/day in all patients and treatment was down-dosed or interrupted according to the drug label. Grade 3/4 AEs, deterioration of liver function and radiologic or symptomatic progression of HCC were criteria for dose modification or interruption.

The median duration of treatment was 3.8 months, 90 patients (30%) were treated for more than 6 months and 41 patients (14%) were treated for more than 12 months.

The overall incidence of AEs was 91%, and 45% of them were of grade 3/4. Fatigue (25%), HFSR (9%), arterial hypertension (7%), weight loss (6%) and diarrhea (6%) were the most frequent severe AEs.

Treatment was down-dosed in 161 (54%) patients (in 133 because of AEs and in 28 because of liver function worsening) and was permanently discontinued in 233 (79%) patients (40% for AEs and 60% for severe liver function deterioration or HCC progression).

Regarding the effectiveness of sorafenib, the SOFIA study reported a median OS of 10.5 months, a finding consistent with the survival observed in patients treated with sorafenib [3, 6]. The OS reported in the 74 BCLC-B patients was longer than that observed in the 222 BCLC-C patients (20.6 versus 8.4 months; P < 0.0001). OS was 21.6 months in the 77 patients treated for more than 70% of the time with a half dose versus 9.6 months in the 219 patients treated for more than 70% of the time with a full dose (P = 0.0006).

The results reported by the SOFIA study, although retrieved in a smaller population respect the global GIDEON study, confirm the safety and effectiveness of sorafenib in a real-life scenario, even with a reduced dose. The effectiveness of half-dose sorafenib might have some implications for clinical practice, especially for a tailored therapy in patients who do not tolerate full-dose treatment. However, the authors of the SOFIA study pointed out the existence of two main caveats for this study, namely the post hoc nature of the analysis of the effectiveness of full- versus half-dose sorafenib and the lack of stratification before treatment of survival predictors.

management of AEs in clinical practice

Sorafenib appeared well-tolerated in both the GIDEON and the SOFIA studies [6, 7]; however, in both real-life studies, a number of AEs were reported. The underlying liver disease and, in particular, its complications can negatively affect the tolerability and the efficacy of sorafenib in HCC patients.

The most frequent sorafenib-associated AEs are dermatological lesions, cancer-related fatigue and diarrhea. Conversely, treatment-related liver AEs are overall less frequently reported. Grade 3/4 liver dysfunction has been reported in the same percentage (3%) of patients assuming sorafenib or placebo in the supplementary appendices of the SHARP trial [4] and in 1% of patients taking sorafenib in the GIDEON study [10].

dermatological lesions

Dermatological lesions, mainly represented by HFSR, are one of the most frequent AEs associated with multi-kinase inhibitors and represent a major cause of dose reductions and/or treatment interruptions. In addition, they determine relevant physical and psychological distress to patients. The early detection of symptoms is crucial and, when possible, preventive measures should be taken in patients with high risk of developing HFSR. Although not tested in clinical trials, some preventive measures are believed to reduce pain, risk of infection and patient discomfort and to avoid the dose reduction or discontinuation of sorafenib (Table 1) [11]. Once established, HFSR can be relieved by symptomatic treatment (Table 1) [11]. As shown in the SHARP study and according to clinical experience, treatment of HFSR may require sorafenib dose reduction or interruption according to the severity of the skin lesions (Table 2) (http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021923s012lbl

Table 1. Techniques identified from the literature for preventing and managing HFSR (reproduced from Edmonds et al. [11], with permission)

  • Prophylactic management
  • Advise patients to have a manicure and pedicure before and during treatment
  • Stress the importance of identifying and reporting skin reactions
  • Advise patients on the frequent prophylactic use of over-the-counter skin emollients
  • Avoid constrictive footwear and excessive friction
  • Wear thick cotton gloves/socks and shoes with padded insoles
  • Symptomatic management
  • Treatment with topical urea singly or plus tazarotene/fluorouracil results in ≥2 grade improvement in the majority of patients
  • Avoid hot water
  • Use thick, intense moisturizing products and anti-itch products (containing 1% dimethicone, 0.1% camphor). Apply creams at least five times a day and any time after hands or feet get wet
  • Dose interruptions at grade 3/4 may be necessary
  • During treatment advise patients to wear comfortable shoes, use shock absorbers for pressure points and relieve pressure on the affected parts
  • Advise patients to avoid excessive sport (e.g. avoid pressure and friction to the affected areas)
  • Advise patients to take cooling hand or foot baths
  • Advise patients to wear two pairs of cotton socks, a thick padded pair as the inner layer and a thinner pair as the outer layer and wear soft shoes and padded insoles
  • Advise patients to wear gloves at night after applying urea- and/or salicylate-containing creams
  • Use non-fragranced products and shower gels instead of soaps
  • Light/topical analgesics may be prescribed for pain relief

Table 2. Dose modifications for skin toxicity (available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021923s012lbl.pdf).

Skin toxicity grade Occurrence Suggested dose modification
Grade 1: Numbness, dysesthesia, paresthesia, tingling, painless swelling, erythema or discomfort of the hands or feet which does not disrupt the patient's normal activities Any occurrence Continue treatment with NEXAVAR and consider topical therapy for symptomatic relief
Grade 2: Painful erythema and swelling of the hands or feet and/or discomfort affecting the patient's normal activities First occurrence Continue treatment with NEXAVAR and consider topical therapy for symptomatic relief.
If no improvement within 7 days, see below
No improvement within 7 days or second or third occurrence Interrupt NEXAVAR treatment until toxicity resolves to grade 0–1
When resuming treatment, decrease NEXAVAR dose by one dose level (400 mg daily or 400 mg every other day)
Fourth occurrence Discontinue NEXAVAR treatment
Grade 3: Moist desquamation, ulceration, blistering or severe pain of the hands or feet or severe discomfort that causes the patient to be unable to work or perform activities of daily living First or second occurrence Interrupt NEXAVAR treatment until toxicity resolves to grade 0–1
When resuming treatment, decrease NEXAVAR dose by one dose level (400 mg daily or 400 mg every other day)
Third occurrence Discontinue NEXAVAR treatment
cancer-related fatigue

Cancer-related fatigue is a multifactorial condition that affects cancer patients before the beginning of therapy, increases during therapy and can persist thereafter. In patients with HCC, the fatigue can be related to liver cirrhosis and cancer. Moreover, treatment-related fatigue may require dose modifications or treatment interruptions. However, the management strategies for preventing or reducing the severity of targeted therapy-related fatigue described in literature were experience-based rather than evidence-based.

Some of the recommendations for managing fatigue are based on ruling out or treating hypothyroidism, anemia, depression and malnutrition. In addition to a possible benefit for treatment-related fatigue, prevention of malnutrition is particularly important in cirrhotic patients with HCC during sorafenib treatment, since reducing the risk of hypoalbuminaemia and muscle catabolism prevents the appearance of ascites and encephalopathy. Treatment-free intervals and dose reductions may be considered in case of grade 3/4 fatigue.

diarrhea

It is important to educate patients on the occurrence and presentation of diarrhea during sorafenib therapy, since an early recognition of this AE may prevent severe diarrhea and its complications.

Sorafenib-induced diarrhea is usually treated with loperamide, based on experience and analogy with chemotherapy-induced diarrhea rather than on clinical studies. In addition to general measures to improve diarrhea such as a low-fiber diet and increased liquid assumption, in cirrhotic patients, lactulose should be stopped, if taken. Dehydration and electrolyte disturbances must be rapidly corrected to avoid the appearance of ascites, renal insufficiency and encephalopathy in cirrhotic patients. For grade 2–4 diarrhea, treatment-free intervals and/or dose reductions may be necessary [4].

sorafenib in patients with Child-Pugh B cirrhosis

It is widely accepted that the natural history of HCC is markedly related to liver function, with a median survival of untreated HCC ∼2.5 times lower in patients with Child-Pugh B cirrhosis versus those with Child-Pugh A cirrhosis [12]. Moreover, liver function may alter the safety of systemic treatments, thereby diminishing the clinical benefit of treated cirrhotic patients [13].

In the SHARP and the Asia-Pacific trials, more than 95% of patients were classified as having Child-Pugh A cirrhosis [4, 5] and the potential benefits of sorafenib in Child-Pugh B patients could not be investigated in those trials. On these bases, a deeper evaluation of the clinical outcomes of Child-Pugh B patients with advanced HCC treated with sorafenib has been advocated [14,15].

Four main studies reported data on patients with Child-Pugh B cirrhosis [12, 1619].

Hollebecque et al. [13] reported the results of a prospective experience on sorafenib efficacy in 120 patients with advanced HCC and 20 of them had Child-Pugh B cirrhosis. The OS in the cohort was 11.1 months with a significantly longer median survival in Child-Pugh A patients than Child-Pugh B patients (13 versus 4.5 months, P = 0.0008). However, statistical analysis did not disclose any correlation among Child-Pugh class and TTP, frequency of AEs and discontinuation of sorafenib. The authors suggested that the shorter OS in Child-Pugh B patients could be attributed, at least in part, to poorer liver function.

Similar results were reported by Kim et al. [16] in an Asian cohort of 225 patients with HCC evaluated according to Child-Pugh score (68 with Child-Pugh B). The disease control rate was higher in patients with Child-Pugh A than Child-Pugh B cirrhosis, but did not differ among patients with Child-Pugh score B7 and those with Child-Pugh score B8 or B9. No differences in the rate of grade 3/4 AEs were reported among patients with different Child-Pugh classes. The authors concluded that patients with Child-Pugh score B7 can be included in future clinical trials, in order to collect further and robust evidence on the treatment with sorafenib in this group of patients. Similar figures on the tolerability were observed by Ozenne et al. [17] in a small cohort of 50 patients with HCC that included 17 patients with a Child-Pugh B cirrhosis.

In the second interim analysis of the GIDEON study, 368 (23%) of 1571 analyzed patients were classified in Child-Pugh B class and 35 patients (2%) in Child-Pugh C class [18]. Overall, sorafenib demonstrated a comparable safety profile in Child-Pugh A and Child-Pugh B patients (Table 3), with the exception of a greater percentage of Child-Pugh B patients who discontinued sorafenib for AEs (38 versus 24%) or who experienced severe AEs (15 versus 8%). In addition, on-treatment deaths were more frequent in Child-Pugh B patients (34 versus 16%), but this finding is likely to be related to severity of liver disease in Child-Pugh B patients.

Table 3. Overview of treatment-emergent safety data by Child-Pugh status in the second interim analysis of the GIDEON study [16]a, reproduced with permission

% of n
Totalb (n = 1571) Child-Pugh A (<7) (n = 957) Child-Pugh B (7–9) (n = 367) Child-Pugh C (>9) (n = 35)
AEs (all grades) 83 82 89 86
Drug-related AEs (all grades) 64 67 63 46
AEs (grade 3/4) 30 29 31 34
Drug-related AEs (grade 3/4) 23 24 22 23
SAEsb 37 29 56 63
Drug-related SAEsc 9 8 15 6
AEs resulting in permanent discontinuation of sorafenibd 28 24 38 51
Deathse 22 16 34 37

aData at study entry.

bChild-Pugh status missing or not evaluable for 56 patients.

cA SAE is defined as any AE occurring at any dose that results in any of the following outcomes: death, life-threatening, hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect and medically important event.

dAny AE.

eTreatment-emergent deaths occurring up to 30 days after last sorafenib dose.

AEs, adverse events; SAEs, serious adverse events.

Pressiani et al. [19] have reported the clinical outcomes obtained in a population of 300 consecutive patients with either Child-Pugh A or Child-Pugh B treated with sorafenib. For patients with Child-Pugh A versus B status, progression free survival was 4.3 versus 2.1 months, TTP was 4.2 versus 3.8 months and OS was 10.0 versus 3. 8 months, and the AE profile was similar in the two groups: these findings suggest that patients with Child-Pugh B liver function can tolerate treatment and may still benefit from sorafenib [19].

As a whole, data collected on the safety of sorafenib in Child-Pugh B patients seem to suggest the potential feasibility of this treatment in this population, taken into account that poorer clinical outcomes are to be expected due to worse liver function. However, more robust studies are necessary before confirm or discard the use of sorafenib in this subset of patients.

dose escalation/reduction with sorafenib

The potential efficacy of sorafenib dose escalation has been reported by the research group of Santoro [20]. In this phase II, randomized trial, 101 patients (selected from the previously described population of 300 patients [19]) with progression of HCC after sorafenib treatment at standard dose (400 mg bid) were assigned to increased-dose sorafenib (600 mg bid) plus best supportive care or to best supportive care alone. Overall, increased-dose sorafenib showed a trend toward an improved progression-free survival (HR: 0.67, 95% CI: 0.43–1.06, P = 0.089), TTP (HR: 0.59, 95% CI: 0.33–1.05, P = 0.070) and OS (HR: 0.71; 95% CI: 0.47–1.08, P = 0.107) versus best supportive care alone, although the results did not reach statistical significance. No differences in the safety profile and in the incidence of AEs were reported between the two arms. According to these results, the authors suggested that increased or standard dose of sorafenib beyond progression should be tested in larger phase II–III trials.

In another preliminary experience on 42 HCC patients, conducted in a clinical-practice setting, Sacco et al. [21] have applied a ‘rump-up’ dosing strategy, which consisted in the administration of sorafenib at a starting dose of 400 mg/day; in the absence of toxicity, this dosage was gradually increased to 800 mg/day after 3 weeks. Despite the number of patients treated with this strategy was limited (n = 13), the clinical outcomes observed following the rump-up administration of sorafenib were comparable with those reported in the overall population, and no grade 3/4 AEs were observed in the rump-up group.

search for biomarkers of response

Biomarkers able to predict patient prognosis or response to therapy may represent a major advance toward a more personalized, tailored treatment in cancer patients [22]. However, HCC is a highly heterogeneous disease and the identification of biomarkers is complex and has been poorly explored so far [22]. The recent EASL-EORTC Clinical Practice Guidelines pointed out that further research in this field is necessary [2].

Llovet et al. [23] have recently reported the results of the analysis on 10 plasma biomarkers potentially implicated in the pathogenesis of HCC and in the response to sorafenib treatment conducted in 491 patients at baseline and in 305 after 12 weeks of treatment in the SHARP trial. The results documented a significant correlation between two angiogenesis biomarkers, Ang2 and VEGF, and survival. In fact, the median survival of patients assigned to sorafenib with low- and high-baseline Ang2 concentrations was 14.1 and 6.3 months, respectively, and the median survival of patients with low- and high-baseline VEGF concentrations was 10.6 and 6.2 months, respectively. None of the plasma biomarkers tested reached statistical significance in predicting response to sorafenib, although a trend toward an enhanced survival benefit from sorafenib was observed in patients with high s-c-KIT or low hepatocyte growth factor concentrations at baseline.

The lack of significant predictors of response to sorafenib was confirmed in another subanalysis of the SHARP trial published by Raoul et al. [24]. In this post hoc analysis, 602 patients were grouped by baseline concentrations of alanine aminotransferase/aspartate aminotransferase, α-fetoprotein (AFP) and bilirubin. Overall, all these markers were associated with a shorter OS in both the sorafenib and the placebo arm, and no differences in the safety profiles were observed among patients with normal versus elevated concentrations of any of these biomarkers. These findings suggest that sorafenib is safe and effective regardless of baseline alanine aminotransferase/aspartate aminotransferase, AFP or bilirubin concentrations. A similar subset analysis of the Asia-Pacific trial reached the same result [25].

Personeni et al. [26] have investigated the prognostic usefulness of a serum AFP response, defined as a >20% decrease in AFP during 8 weeks of treatment with sorafenib and compared it with the RECIST criteria. In total, 32 of 85 patients (37.6%) were classified as AFP responders, whereas 58 of 82 patients (70.7%) achieved disease control according to the RECIST criteria. Statistical analysis showed that only AFP response (HR = 0.52; P = 0.009) and Cancer of the Liver Italian Program dichotomized stage (HR = 0.42; P = 0.002) are prognostic factors of survival. According to these findings, authors concluded that the assessment of AFP response may be considered as an alternative to RECIST to monitor sorafenib activity in HCC [26].

conclusions

Sorafenib was the first agent that demonstrated a benefit on survival of patients with advanced HCC and is currently the standard treatment of this disease.

Despite the robustness of the results collected in randomized clinical trials, which represent the basis for the evaluation of efficacy and safety for each new drug, the importance of observational studies and clinical practice experience is increasing in the current scientific debate. In fact, observational studies offer a chance to unravel the safety and toxicity of a given drug in clinical practice and are able to expand upon the findings of phase III trials.

The main clinical practice studies conducted so far, namely the GIDEON and SOFIA studies, confirm the benefit of sorafenib on OS, which was previously observed in RCTs. The safety profile of sorafenib was similar, although a slightly higher rate of AEs and need for dose reduction was reported when compared with the landmark phase III trials. However, this finding may be attributed, at least in part, to the presence of multiple concomitant conditions in patients included in the observational experiences. In addition, a proper management of sorafenib-associated AEs reduces the risk of dose reductions and/or treatment interruptions, thus optimizing the clinical benefits associated with this molecule.

The results of the global GIDEON study, albeit still preliminary, suggest that whenever possible, full dose of sorafenib should be maintained. However, if severe AEs occur, dose could be reduced without decreasing effectiveness, as documented in the SOFIA study. It will be of great interest to identify the clinical, laboratory and genetic characteristics of these patients.

New indications and treatment modalities of sorafenib are being explored by current research. In particular, the effectiveness and safety of this molecule in Child-Pugh B patients deserve, in our opinion, further investigations. The results collected show poorer outcomes in patients with Child-Pugh B cirrhosis treated with sorafenib, when compared with patients with Child-Pugh A cirrhosis. However, this finding can be likely attributed to a more severe liver dysfunction and more compromised conditions of these patients and not to an effect of the drug itself. Noteworthy, available evidence is consistent in showing that the safety profile of sorafenib is comparable in Child-Pugh A and Child-Pugh B patients. An alternative treatment approach could be the administration of increased-dose sorafenib in patients with HCC progression, but this therapeutic scheme has been investigated only in one trial, and therefore, we believe that additional research on its efficacy and safety is advisable.

Lastly, the results of subset analyses of the registrative trials consistently show that the efficacy and safety of sorafenib are maintained irrespective of several biochemical parameters observed at baseline. This result supports the use of sorafenib in different classes of liver disease severity. However, we think that, in the future, the identification of biomarkers predicting prognosis of HCC and/or response to sorafenib or other treatments for this condition may facilitate a more personalized treatment of oncological patients. Further investigation on the potential use of sorafenib in the adjuvant setting is ongoing (the STORM study; NCT00692770), and it will provide new information on the use of sorafenib after surgical resection or local ablation.

funding

Editorial assistance was provided by Luca Giacomelli, PhD, on behalf of inScience Communication, Springer Healthcare; this assistance was funded by Bayer Italy.

disclosure

CV has received research funding from Bayer. Other authors declare no conflict of interest directly relevant to this paper.

references

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