Galectin Stands Out in 2013 with Liver Fibrosis Drug

Oct. 14, 2013, 12:06 p.m. EDT

Oct 14, 2013 (ACCESSWIRE via COMTEX) -- Biotechnology has been an outperforming sector in 2013 with IBB, iShares Nasdaq Biotechnology Index Fund, rising about 57 percent through September 27 highs. BIB, the ProShares Ultra Nasdaq Biotechnology Index has roared ahead about 135 percent through highs on the same day.

While those gains are certainly robust, the September high of Galectin Therapeutics Inc. at $13.21 made them seem paltry, producing gains of more than 550 percent in 2013 for GALT shareholders. The surge in Galectin's valuation seems simply a product of corporate advancements as the company establishes itself as a leader in pioneering treatments for fibrosis, especially liver fibrosis that results from fatty liver disease.

Liver fibrosis can be an asymptomatic death sentence with no available therapeutics to treat the scarring in the liver that leads to liver complications, co-morbidities and death. The genesis of fibrosis is fatty liver disease, with the combined conditions, called non-alcoholic steatohepatitis, or "NASH," affecting as many as 15 million Americans today. Some estimates put the number of Americans affected by nonalcoholic fatty liver disease (NAFLD) as high as 30 percent of the population, or approximately 94 million people.

With the high diagnosis rate, researchers have mostly focused on developing therapies to stop the accumulation of fat in the liver, but with limited success. Companies devoting their resources toward new treatments for advanced stages of the diseases are minimal, with Galectin and Gilead Sciences +0.03% running promising programs in that space. Meanwhile, the select few other companies targeting fibrosis are focused on the early stages of the disease, a time where it can be very difficult to identify which patients will advance to more serious stages of the disease. Gilead has received plenty of attention in 2013 for its leadership role in HIV drugs as well as fibrosis efforts with simtuzumab in mid-stage trials for NASH patients, helping send shares about 70 percent higher so far this year.

While Galectin has its GM-CT-01 drug candidate in Phase 2 clinical trials for melanoma, perhaps an even larger driver has been their research of their galectin protein-inhibiting drugs that shows the potential for GR-MD-02 to not only treat NASH patients, but also actually reverse the scarring in the liver. A drug to treat fatty liver disease and fibrosis has blockbuster potential written all over it, but one that can actually reverse scarring can revolutionize fibrosis research.

While this article is only referencing the liver, fibrosis is prominent in other vital organs as a result of inflammation or damage, such as the lungs, heart, intestines and more. Galectin has conducted pre-clinical research on GR-MD-02 to expand into additional indications, with information released in September disclosing the drug showing a "robust effect" in reducing lung fibrosis. Separate research has also demonstrated tumor shrinkage and enhanced survival in immune competent breast and prostate cancer mouse models treated with GR-MD-02 in combination with immune checkpoint blockage inhibitors anti-CTLA-4 or anti-PD-1.

Galectin is evaluating GR-MD-02 in the Phase 1 trial under a Fast Track designation from the Food and Drug Administration with the first patient dosed in July. The trial is planned to enroll about 32 patients with NASH and stage 3 fibrosis across six clinical sites in the U.S.

There is no doubt that the biotech sector has been one of the best market performers in 2013 and it doesn't look to be losing any steam. Even as some of the majors take a breather as the new year approaches, investors should be looking for developmental companies that are starting to grow a stronger valuation based upon two things: the data supporting their drug and the future market potential if successfully maneuvered down the regulatory pathway. In the case of companies engaged in fibrosis treatments, market capitalizations in the low hundreds of millions of dollars should only represent a portion of the things to come.

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College of Medicine helps with groundbreaking program to provide mobile Hepatitis C testing

October 16, 2013

Dr. Stacey Toomskin (left) with second-year medical student Katrina Castille.

A white van large enough to fill three parking spaces pulls into a southwest Philadelphia neighborhood. Several Drexel medical students and other volunteers emerge, led by Drexel Medicine’s Stacey Trooskin, M.D., Ph.D., assistant professor in the Division of Infectious Diseases and HIV Medicine. Traveling in pairs, the volunteers begin canvassing up and down the street within a two-block radius, encouraging local residents to “Do One Thing”: come out to the van – a mobile lab – for a free and easy test for hepatitis C (HCV) and HIV. 

Trooskin and the College of Medicine are collaborating with Amy Nunn, Sc.D., of Brown University’s Alpert Medical School in the “Do One Thing, Change Everything” campaign, aimed at combating not only HCV, but also HIV, in medically underserved communities.

One of the first of its kind nationwide, the campaign aims to dramatically stimulate HCV and HIV testing in communities with high rates of infection. The approach focuses on the neighborhood as the unit of intervention, rather than the individual. Philadelphia is serving as the campaign’s model city, with plans to offer it in other cities in the future. The program’s unique mobile lab offers free, rapid testing for both diseases.

“Hepatitis C is a hidden disease in many urban communities because of misconceptions about the disease and lack of access to testing and care,” Trooskin said. “So, many people may be infected and simply don’t know it. This campaign is aimed at tackling these issues through the rapid, mobile testing lab and through community education.”

Every week, the mobile lab goes out in the community, methodically visiting every block in a ZIP code identified as having high rates of infection. Trooskin and her colleagues use geographic information systems software to track their progression through the neighborhoods, making sure no street is missed. Among the methods they use to publicize their location is a constant Twitter feed.

Before bringing the mobile lab into a neighborhood, the “Do One Thing” team mobilizes the community by meeting with block captains, local clergy, and local businesses, asking them to support and encourage HCV testing among their neighbors, congregations, or customers.

Drexel medical students learn important lessons about community medicine by participating in the campaign as part of their community experience requirement or as volunteers in a program called Bridging the Gaps. During the spring 2013 semester, 10 students participated; currently, two are volunteering. Students from the School of Public Health also volunteer. After walking the area with flyers to encourage testing, students doing outreach go door to door in pairs.

The campaign’s goal for individuals who test positive for HCV is follow-up RNA testing to confirm a chronic infection. According to a study by the Centers for Disease Control and Prevention, about half of reported hepatitis C cases in the United States had only an HCV antibody test and did not follow up with confirmatory testing.

“To improve the identification of chronic infections and link more chronically infected people into care, confirmatory RNA testing is crucial,” Trooskin said, noting that CDC guidelines have recently been changed to reflect this. During the campaign, if the rapid test is positive, a trained phlebotomist in the van can draw blood for RNA testing. Through an agreement with Hahnemann University Hospital, the mobile testing unit can deliver HCV blood tests to the hospital’s labs at any time of day or night for processing within the required six-hour window.

“We encourage individuals who test positive to engage in care and learn about secondary prevention and treatment options so HCV doesn’t progress further and cause advanced liver disease,” says Trooskin.

The campaign has experienced HCV test technicians who also act as patient navigators to help engage patients in care. These patient navigators will meet individuals at predetermined locations such as the person’s home, a subway stop or another spot selected by the patient, where they share the follow-up test results and offer to escort them to Drexel Medicine’s Partnership Comprehensive Care Practice for treatment, if indicated.

“Our patient navigators have even tracked people down who are living in abandoned houses to ensure they get care,” relates Trooskin. “Many people who test positive have never had a primary care provider before, so we go through a process of building trust before they will agree to confirmatory testing and treatment.”

Since the College of Medicine began the collaboration in December 2012, 780 individuals have been tested, and 31 had a reactive HCV antibody test. Of those, 25 have already been seen by Trooskin at the Partnership, have an appointment scheduled, or are working with the practice social worker to get insurance coverage for treatment. Of the other six, four had cleared the virus on their own, and two were already linked to care at another clinic.

Many individuals may have had HCV for a while but don’t understand the importance of getting care, or they have the misconception that there is no treatment for HCV, according to Trooskin. However, current treatment regimens for those with HCV can cure more than half of those infected, and even more effective therapies are in the drug development pipeline.

“We are excited about our campaign results so far,” says Trooskin. “This innovative effort could put Philadelphia on the map in terms of increasing access to HCV care.”

For more campaign information, visit 1nething.com.

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Clear Link Between Liver Disease and Risk for Cardiovascular Disease, Finds Saint Luke's Study

Assessment of 377 asymptomatic patients reveals non-alcoholic fatty liver disease (NAFLD) proves to be a stronger indicator than age, smoking, gender, or other traditional risk factors

KANSAS CITY, Mo., Oct. 16, 2013 /PRNewswire-USNewswire/ -- Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the United States and other Western countries, affecting up to a third of the general population, and in most cases causing no signs or symptoms. NAFLD is the most common cause for cirrhosis and a common cause for primary liver cancer. Most affected individuals are completely unaware of their liver disease.

Now Saint Luke's liver specialists and cardiologists have discovered a compelling association between NAFLD and a high risk for cardiovascular disease. The link between the two was stronger than other more traditional risk factors for coronary artery disease such as smoking, hypertension, male gender, diabetes, high cholesterol, or metabolic syndrome. The research findings are published in an online article in the Mayo Clinic Proceedings posted Oct. 16, 2013.

The research study was a collaborative partnership between Saint Luke's Liver Disease Management Center gastroenterologists Rajiv Chhabra, M.D., and John Helzberg, M.D., and Saint Luke's Mid America Heart Institute cardiologists James O'Keefe, M.D., and Randall Thompson, M.D.

The study assessed upper abdominal CT images from 377 non-symptomatic patients undergoing non-contrast CT scans to determine coronary calcium scores. Using expanded imaging "windows" to include the liver and spleen, researchers found that patients with fatty liver disease were more likely to also have coronary artery disease. The research is compelling enough that cardiologists at Saint Luke's are considering changing their practices to include liver and spleen images in CT scans as a screening indicator of coronary artery disease risk.

Non-alcoholic fatty liver disease is the accumulation of fat in the liver in people who drink little to no alcohol. The fat can cause inflammation and scarring in the liver. Its most serious form can progress to cirrhosis, liver failure, or liver cancer. It is the most common liver disorder in Western countries and one of the fastest growing concerns among clinicians due to an escalating patient population with obesity and diabetes. 

"If current trends continue, the prevalence of NAFLD is expected to increase to 40 percent of the population by 2020," said Dr. Helzberg. "This discovery is important in identifying potential cardiovascular disease in NAFLD patients. Hopefully future research will yield better treatment options and disease management."  Treatments now primarily include lifestyle changes such as diet, exercise, and increased monitoring.

While more research is needed to explore the relationship between the two conditions, the growing number of patients with NAFLD suggests a potential role for increased screening among the medical community. "These findings suggest that patients with coronary artery disease should possibly be screened for liver disease. Likewise, NAFLD patients should be evaluated for coronary artery disease," said Dr. Chhabra.

Funding was provided through a research grant to Dr. Helzberg from the Saint Luke's Foundation and the Mid America Heart Institute Foundation.

"This study is another example of what can arise from cross-disciplinary collaboration that is increasingly common at Saint Luke's. By pooling our knowledge and insights, we are able to identify promising areas for research that may have a powerful impact on our ability to practice medicine and to improve the lives of our patients," said David J. Cohen, M.D., M.Sc., director of Cardiovascular Research at Saint Luke's Hospital.  

About Saint Luke's Liver Disease Management Center
At Saint Luke's Liver Disease Management Center, patients throughout the Midwest and across the United States have access to liver disease treatment options provided by a multidisciplinary physician group. From preventive care to liver transplantation, Saint Luke's provides a full range of services for patients with disorders of the liver, bile ducts, and pancreas.

About Saint Luke's Mid America Heart Institute
Saint Luke's Mid America Heart Institute, a member of Saint Luke's Health System and a teaching affiliate of the University of Missouri-Kansas City, is one of the preeminent cardiovascular programs in the country. Its legacy of innovation began more than 25 years ago when it opened as the nation's first heart hospital. Since then, the Heart Institute has earned a world-wide reputation for excellence in the treatment of heart disease, including interventional cardiology, cardiovascular surgery, imaging, heart failure, transplant, heart disease prevention, women's heart disease, electrophysiology, outcomes research, and health economics.  With more than 50 full-time board certified cardiovascular specialists on staff, the Heart Institute offers one of the largest heart failure/heart transplant programs in the country, has the largest experience with transcatheter aortic valve replacement in the Midwest, and is a global teaching site for the newest approaches to opening challenging blocked arteries using minimally invasive techniques.

SOURCE Saint Luke's Hospital of Kansas City

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Danoprevir Combo Cuts Hep C Viral Load

Gastroenterology

Published: Oct 16, 2013

By Cole Petrochko, Staff Writer, MedPage Today

Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania

Action Points

• The addition of danoprevir to the combination peginterferon alfa-2a and ribavirin in a randomized study led to high rates of sustained virologic response in patients with hepatitis C virus genotype 1 infection.
• Note, however, that some of the patients receiving high doses of danoprevir had grade 4 increases in alanine aminotransferase.

The addition of danoprevir to peginterferon and ribavirin therapy for hepatitis C increased patients' sustained virologic response, researchers found.

In a phase II trial of danoprevir as an add-on therapy for peginterferon alfa-2a and ribavirin, sustained virologic response was achieved in 68% of those who received 300 mg of the drug, 85% of those who received 600 mg, and 76% in those who received 900 mg, versus 42% in those who received placebo, according to Patrick Marcellin, MD, PhD, of Hôpital Beaujon in Clichy, France, and colleagues.

Serious adverse events were also less common among those treated with danoprevir, with 7% to 8% of those who received drug treatment experiencing serious adverse events versus 19% of those who received placebo, they wrote online in the October issue of Gastroenterology.

Danoprevir is a second-generation protease inhibitor. A pilot trial in 2009 showed that danoprevir combination treatment with mericitabine was associated with dramatic decreases in viral load at 13 days.

The clinical trial randomized 225 treatment-naive hepatitis C genotype 1 patients to one of three danoprevir treatment groups -- 300 mg every 8 hours, 600 mg every 12 hours, or 900 mg every 12 hours -- or to placebo with peginterferon alfa-2a and ribavirin for 12 weeks.

After week 12, patients continued treatment with peginterferon alfa-2a and ribavirin for an additional 12 to 36 weeks. Those who experienced extended rapid virologic response -- defined as undetectable hepatitis C virus (HCV) RNA at weeks 4 to 20 -- discontinued therapy after 24 total weeks.

Efficacy endpoints included sustained undetectable viral load at 23 weeks of untreated follow-up, virologic response rates over time, relapse rates, and sustained virologic response in those who had an extended rapid virologic response. Researchers also looked at response based on HCV RNA analysis through serum measures every few weeks through week 48 of treatment, as well as at weeks 4, 12, and 24 of untreated follow-up.

Patients were mostly white (84% to 88%), had a mean age of 47 to 50, and had HCV RNA levels of 800,000 IU/mL or greater.

After the first week of drug treatment, mean HCV RNA decreases ranged from 3.95 to 4.28 log₁₀ IU/mL versus 0.77 log₁₀ IU/mL with placebo treatment, and mean maximum reductions occurred after 4 to 6 weeks of drug treatment "and were sustained throughout the first 24 weeks of treatment in danoprevir-treated patients," the investigators reported.

Compared with placebo, danoprevir treatment increased on-treatment virologic response rates and sustained virologic response, and decreased relapse rates.

Investigators also found:

• Among those who experienced extended rapid virologic response, sustained virologic response was achieved in 87% of those receiving 300 mg of danoprevir and in 96% of those receiving 600 mg.
• Relapse occurred in 18%, 8%, and 11% of those treated with 300 mg, 600 mg, and 900 mg of danoprevir, respectively, versus 38% of those receiving placebo.
• There was also a "consistently higher sustained virologic response rate" among drug-treated patients with IL28B CC genotype disease.

Types of adverse events were similar between drug versus placebo treatment groups, and common events included fatigue, headache, nausea, insomnia, myalgia, and chills. Incidence of nausea, diarrhea, and vomiting "increased in a dose-related manner" among drug recipients.

Neutropenia occurred in 6% to 13% of danoprevir group participants versus 10% of placebo recipients. Hemoglobin of <10 g/dL and <8.5 g/dL occurred in 19-24% and 1-4% of participants, respectively, versus 35% and 6% of those who received placebo.

Four patients given danoprevir (one in the 600-mg group and three in the 900-mg group) had reversible, grade 4 increases in alanine aminotransferase, which led to early discontinuation of the 900-mg arm of the study.

The study was limited by a low number of black patients, exclusion of patients with advanced fibrosis and cirrhosis, and randomization that did not stratify for IL28B genotype or HCV subgenotype.

The study was supported by F. Hoffmann-La Roche.

The authors received support from Roche, Gilead, BMS, Vertex, Novartis, Janssen-Tiboted, MSD, AbbVie, Boehringer Ingelheim, Pfizer, Allos BioPharma, Merck, Genentech, Hyperion, Bayer, Bristol-Myers Squibb, Kadmon, Idenix, Salix, Sundise, Genfit, Astellas, GlaxoSmithKline, Medtronic, Santaris, Rottapharm-Madaus, Achillion, MSD Austria, Janssen Austria, BMS Austria, and Roche Austria.

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Primary source: Gastroenterology
Source reference: Marcellin P, et al "Randomized controlled trial of danoprevir plus peginterferon alfa-2a and ribavirin in treatment-naive patients with hepatitis C virus genotype 1 infection" Gastroenterology 2013; 145: 790-800; DOI: 10.1053/j.gastro.2013.06.051.

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A Breakthrough for Hepatitis C (Video) : Better treatment in less time

Cleveland Clinic News Wire | Digestive Health | Living With Chronic Conditions

No. 4 Innovation: A Breakthrough for Hepatitis C (Video)

 

Better treatment in less time

By News Wire Team | 10/16/13 11:06 a.m.

Cleveland Clinic asked more than 100 of its top experts about the innovations set to reshape healthcare in the coming year. These are their answers — the Top 10 Innovations for 2014.

For the 4 million people in the United States with a hepatitis C infection, treatment options have improved greatly in the past three years.

Until 2011, there were no proven medicines for patients who didn’t respond to traditional therapy for this liver disease. That year, two new drugs— telaprevir and boceprevir—made Cleveland Clinic’s top 10 innovations list and changed the prospects for patients in need. This year, yet another promising option makes the list: sofosbuvir, the first all-oral hepatitis C treatment.

 

Shorter, safer and easier to tolerate

Sofosbuvir is moving through the final stages of FDA approval. Its promise includes the highest cure rates ever, reduced treatment time and fewer side effects.

“Its promise includes the highest cure rates ever, reduced treatment time and fewer side effects.”

This medication would be the first of a new generation of hepatitis C drugs called direct-acting antivirals (DAA). DAAs can improve what for many has been a very difficult treatment regimen — one that can take up to 48 weeks and requires injections of interferon, a drug that is difficult to tolerate.

More important, DAAs can improve treatment response rates to 90 percent or higher. Sofosbuvir — and other DAAs in the pipeline — also are more tolerable and safer.

Even better, they reduce the treatment length to 12 weeks.

Source

Bristol-Myers Squibb launches initiative to support search for cure in chronic viral diseases

Partnering for Cure to kick off with debate on HIV cure at European AIDS conference

(PARIS, France, October 16, 2013) – Bristol-Myers Squibb (BMS) announced today at the 14^th European AIDS Conference (EACS) in Brussels the launch of Partnering for Cure, a scientific initiative to support education and research and to transform clinical outcomes for patients with chronic viral diseases, namely HIV, hepatitis B (HBV) and hepatitis C (HCV).  The initiative, which confirms BMS’ commitment in virology, is rooted in the company’s legacy in virology and ongoing research in HIV and viral hepatitis.

The Partnering for Cure initiative is led by an expert panel of clinical and research experts from across Europe, including Germany, France, Switzerland, Sweden, Belgium, Italy, Spain and the UK. Composed of three core components – education, scientific exchange and scientific research – the programme will focus on reviewing current treatment paradigms, providing a forum for discussion on the evolution of treatment towards cure and facilitating research seeking novel cure pathways in chronic viral diseases.

Following a first meeting in six sites on September 16, today’s Partnering for Cure satellite symposium at EACS will put HIV cure ‘on trial’, with faculty members arguing for and against the case that cure is possible. Audience members will be given the opportunity to vote on the evidence presented.

“We need this programme: a programme to cure HIV, HBV and HCV,” said Christine Katlama, Partnering for Cure Faculty Chair, from the Hôpital Pitié-Salpêtrière in Paris. “We have so many patients across the world and we need a cure. The answer is in the lab, the answer is also in the clinical field and there is a lot to do. We need to move forward and work together and Partnering for Cure is a fantastic opportunity to do just that.”

Chronic viral infections make a substantial contribution to the burden of chronic diseases and premature mortality worldwide.  In December 2012, the Global Burden of Disease Study reported 1,465,000 deaths caused by HIV/AIDS and 1,445,000 deaths caused by viral hepatitis in 2010.[i] Infections with hepatitis B and C viruses also cause an estimated 57% of cases of liver cirrhosis and 78% of cases of primary liver cancer annually.[ii] Whilst important advances have been made over the last decade, particularly in HIV, significant unmet needs and the opportunity for cure remains.     

Bristol-Myers Squibb has been actively involved in virology research and development since the 1980s, initially focusing on HIV but more recently on HBV and HCV. “This is an important and ambitious programme that reflects our genuine engagement in virology,” said George Hanna, Vice President, HIV Development, Bristol-Myers Squibb. “It is a way to showcase the BMS commitment to cure in chronic viral infections and to advance investigational compounds - with novel mechanisms of action - that aim to address unmet clinical needs in HIV, HBV and HCV. Along with our ongoing research in virology, we remain steadfast in our pursuit of partnership platforms with policy, advocacy and healthcare professional stakeholders.”

As part of the Partnering for Cure programme, Bristol-Myers Squibb will also support three independent research projects focused on improving current understandings of HIV, HBV and HCV and creating novel treatment and cure strategies. Research applications will be accepted via the website, www.bms.com/israpplications until October 31, 2013 and will be subject to blind evaluation by the Partnering for Cure faculty. 

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About Bristol-Myers Squibb

Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases.

Bristol-Myers Squibb Virology Support Programmes

Like Partnering for Cure, Bristol-Myers Squibb supports a number of scientific and educational programmes within the virology community around the world that encompass disease education, disease awareness and sharing of best practices. These include SHE® (Strong, HIV positive, Empowered Women/Strong, HIV positive Women Educational Programme), a comprehensive and innovative programme for women living with HIV and their healthcare providers  and PATH B® (Patients and professionals acting together for hepatitis B), a joint initiative between hepatitis patient groups and hepatologists to provide comprehensive information and support for patients with chronic hepatitis B.

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Media: Celine Van Doosselaere  +33 (6) 14 77 34 31  celine.vandoosselaere@bms.com

References

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[i] Global Burden of Disease Study 2010, The Lancet, Volume 380, No9859, Dec 15, 2012, p2053-2260 

[ii] WHO and WHA, Global Policy Report on the Prevention and Control of Viral Hepatitis, 2013, 
http://global-report.worldhepatitisalliance.org/en/home.html

Source

Host-targeting agents in the treatment of hepatitis C: A beginning and an end?

Antiviral Res. 2013 Sep 30. pii: S0166-3542(13)00268-4. doi: 10.1016/j.antiviral.2013.09.020. [Epub ahead of print]

Baugh JM, Garcia-Rivera JA, Gallay PA.

Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA.

Abstract

The development of two distinct classes of hepatitis C antiviral agents, direct-acting antivirals (DAAs) and host-targeting antivirals (HTAs), have distinctly impacted the hepatitis C virus (HCV) field by generating higher sustained virological response (SVR) rates within infected patients, via reductions in both adverse side effects and duration of treatment when compared to the old standard of care. Today DAAs are actively incorporated into the standard of care and continue to receive the most advanced clinical trial analysis. With a multitude of innovative and potent second-generation DAA compounds currently being tested in clinical trials, it is clear that the future of DAAs looks very bright. In comparison to the other class of compounds, HTAs have been slightly less impactful, despite the fact that primary treatment regimens for HCV began with the use of an HTA - interferon alpha (IFNα). The compound was advantageous in that it provided a broad-reaching antiviral response; however deleterious side effects and viral/patient resistance has since made the compound outdated. HTA research has since moved onward to target a number of cellular host factors that are required for HCV viral entry and replication such as scavenger receptor-BI (SR-BI), 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCoA reductase), cyclophilin A (CypA), fatty acid synthase (FASN) and miRNA-122. The rationale behind pursuing these HTAs is based upon the extremely low mutational rate that occurs within eukaryotic cells, thereby creating a high genetic barrier to drug resistance for anti-HCV compounds, as well as pan-genotypic coverage to all HCV genotypes and serotypes. As the end appears near for HCV, it becomes important to ask if the development of novel HTAs should also be analyzed in combination with other DAAs, in order to address potential hard-to-treat HCV patient populations. Since the treatment regimens for HCV began with the use of a global HTA, could one end the field as well?

Copyright © 2013. Published by Elsevier B.V.

KEYWORDS: Alisporivir, Cyclophilin A, HCV, Host-targeting antivirals

PMID: 24091203 [PubMed - as supplied by publisher]

Source

What is hepatitis? Dangerous infections a worldwide health threat

Premium Health News Service
4:30 a.m. CDT, October 16, 2013

http://www.whatdoctorsknow.com

Together, hepatitis B and C represent one of the major threats to global health. Hepatitis B and C are both 'silent' viruses, and because many people feel no symptoms, you could be infected for years without knowing it. If left untreated, both the hepatitis B and C viruses can lead to liver scarring (cirrhosis).

If you have liver cirrhosis, you have a risk of life-threatening complications, such as bleeding, ascites (accumulation of fluid in the abdominal cavity), coma, liver cancer, liver failure and death. In the case of chronic hepatitis B, liver cancer might even appear before you've developed cirrhosis.

In some cases, a diagnosis is made too late and the only option is a liver transplant. If you think you've been at risk, it's important to get tested as soon as possible and consider your treatment options and self-management strategies.

Patients with hepatitis B infection can also be infected with a second virus known as hepatitis delta virus, hepatitis D virus or simply HDV. (Find out more about hepatitis D at hepatitis-delta.org)

THE DIFFERENCE BETWEEN HEPATITIS B AND C

1. While there is a vaccine that protects against hepatitis B infection, there's no vaccine available for hepatitis C
2. Both viruses can be contracted though blood-to-blood contact
3. Hepatitis B is more infectious than hepatitis C and can also be spread through saliva, semen and vaginal fluid
4. In the case of hepatitis B, infection can occur through having unprotected sex with an infected person. Please note that this is much rarer in the case of hepatitis C
5. While unlikely, it is possible to contract hepatitis B through kissing. You cannot contract hepatitis C through kissing
6. Neither virus is easily spread through everyday contact. You cannot get infected with hepatitis B or C by shaking hands, coughing or sneezing, or by using the same toilet. There are different treatments for the two viruses. While treatment can control chronic hepatitis B, it can often cure hepatitis C
7. Even if treatment is not an option for you, you can do something about your disease. A healthy lifestyle is important. Alcohol, smoking, eating fatty foods, being overweight or extreme dieting (eating no food at all) may worsen your liver disease. Therefore, try to avoid all alcohol, stop smoking, eat a low fat diet with enough fruit and vegetables, and reduce your weight if necessary

HEPATITIS B

The World Health Organization recognizes that hepatitis B is one of the major diseases affecting mankind today. Hepatitis B is one of the most common viral infections in the world and the WHO estimates that two billion people have been infected with the hepatitis B virus and approximately 350 million people are living with chronic (lifelong) infections. An estimated 500,000 to 700,000 people die every year from hepatitis B.

The hepatitis B virus is highly infectious and about 50-100 times more infectious than HIV. In nine out of 10 adults, acute hepatitis B infection will go away on its own in the first six months. However, if the virus becomes chronic, it may cause liver cirrhosis and liver cancer after up to 40 years, but in some cases as little as five years after diagnosis.

The hepatitis B virus is transmitted between people through contact with the blood or other body fluids (i.e. saliva, semen and vaginal fluid) of an infected person. Although not all people will have any signs of the virus, those that do may experience the following symptoms:

1. Flu-like symptoms
2. Fatigue
3. Nausea
4. Jaundice (yellowing of the skin)
5. Stomach ache
6. Diarrhea/dark urine/bright stools
7. Aching joints

Unlike hepatitis C, there is a vaccine that can prevent infection. If you think you're at risk, you should get vaccinated as soon as possible.

HEPATITIS C

Hepatitis C is different from hepatitis B in that the virus more frequently stays in the body for longer than six months, and therefore becomes chronic. Four out of five people develop a chronic infection, which may cause cirrhosis and liver cancer after 15-30 years. There are approximately 170 million people chronically infected with hepatitis C worldwide. In 2000, the WHO estimated that between three and four million people are newly infected every year.

Hepatitis C is mainly spread through blood-to-blood contact and, like hepatitis B, there are often no symptoms. Symptoms that do occur can include:

1. Flu-like symptoms
2. Fatigue
3. Nausea
4. Aching muscles and joints
5. Anxiety and depression
6. Poor concentration
7. Stomach ache
8. Loss of appetite
9. Dark urine/bright stools

PREVENTION

The hepatitis B virus (HBV) is transmitted between people through contact with the blood or other body fluids (i.e. saliva, semen and vaginal fluid) of an infected person. Please note that it's very unlikely it can be contracted through kissing or sharing cutlery. The hepatitis C virus (HCV) is spread through direct contact with infected blood. Very rarely it may be passed on through other body fluids.

Most common routes of transmission for hepatitis B or C viruses include:

1. Blood transfusions and blood products using unscreened blood (in most countries, but not all, blood has been screened since about 1990)
2. Medical or dental interventions without adequate sterilization of equipment
3. Mother to infant during childbirth
4. Sharing equipment for injecting drugs
5. Sharing straws, notes etc. for snorting cocaine
6. Sharing razors, toothbrushes or other household articles
7. Tattooing and body piercing if done using unsterilized equipment

In the case of hepatitis B, infection can also occur through having unprotected sex with an infected person. If you think you could have been at risk from either hepatitis B or C, it's important to get tested.

Getting immunized is the best way of preventing hepatitis B infection. More than one billion doses of the hepatitis B vaccine have been used since the early 1980s and it has been shown to be effective in approximately 95 percent of cases. There's currently no vaccine for hepatitis C.

TESTING AND DIAGNOSIS

To diagnose hepatitis B the blood needs to be checked for the HB surface antigen (HBsAg). The HBs antigen is a part of the virus and will usually appear in your blood six to twelve weeks after infection. If the test is positive, you have hepatitis B. In that case, your doctor should conduct further tests to check if your hepatitis B infection is new or old, if it is harming your body or not, and if you need treatment or not.

If you've naturally cleared the virus, or if you've been vaccinated against hepatitis B, you will have antibodies to hepatitis B (anti-HBs). Your body made these to destroy the virus. It's good to have anti-HBs, because that means you're protected against future infection by the hepatitis B virus.

For hepatitis C, your doctor will first check for HCV antibodies (anti-HCV). If the test is positive, this means you either have the virus now, or have had the virus and cleared it. Hepatitis C antibodies usually take 7-9 weeks to appear in your blood after infection.

If your immune system is weakened (e.g. by HIV) your body may take longer to produce HCV antibodies, or it may not produce any at all. If the first test is positive, your doctor will then test for the virus itself (HCV RNA). If this is positive, you have hepatitis C.

If you are diagnosed with hepatitis B or C, you'll face many challenges, but it's better to confront the disease head on, know how to avoid transmitting the infection to others and consider your treatment options and self-management strategies as early as possible.

For further information about whether you might be, or have been, at risk and how you can get tested, please contact your local patient group, who will be able to provide you with the information that you need.

HEPATITIS B TREATMENT

Acute hepatitis B: It is not usually necessary to treat a new hepatitis B infection in the first six months. Nine out of ten new infections go away on their own, with or without treatment. In this early stage of disease, treatment makes very little difference to the chances of a cure. Antiviral drugs may only be necessary and helpful in rare cases, if the acute infection causes very aggressive liver inflammation.

Chronic (long-lasting) hepatitis B: consult with your doctor about your situation. Some people need treatment, while others should wait. Treatment does not usually cure you of hepatitis B, but it can turn an 'aggressive' hepatitis B infection into a mild infection. This can stop the liver from being damaged. If the infection is considered mild, it might be better to monitor it and wait until later for treatment. You can treat chronic hepatitis B with peg-interferon or with pills, which are called nucleoside or nucleotide analogues.

Peg-interferon alfa comes in a syringe and stimulates the immune system against the virus. This treatment may have side effects, such as fatigue, flu-like symptoms, depression, skin and hair problems and changes in blood chemistry, amongst others.

Treatment continues for 24-48 weeks and while not all hepatitis B patients respond well to interferon, certain types of hepatitis B infection do. For example, patients with genotype A, HBeAg positive, with elevated liver enzymes but NO cirrhosis can often successfully reduce their viral infection to a milder state.

Your doctor needs to monitor your interferon treatment closely. Interferon treatment should not be used if you already have cirrhosis of the liver.

Nucleoside and nucleotide analogues come in pills. They stop the virus from replicating. The pills have very few side effects, and even patients with cirrhosis can take them. However, patients need to take their pills every day for several years, sometimes a lifetime.

If the virus becomes resistant to one type of pill, it might stop working, and another, different drug will need to be added to their treatment to get the virus back under control. Your doctor should monitor your viral load (HBV DNA) to make sure your treatment works.

Don't forget to take your pills, even if you feel well. If you miss many doses or stop treatment too early, the disease might become worse than it was before.

HEPATITIS C TREATMENT

In many countries, the second quarter of 2011 marked the arrival of a new current standard of care for people with HCV genotype 1; Boceprevir (Victrelis) and Telaprevir (Incivek), which are protease inhibitors taken orally and added to the Pegylated interferon alfa and ribavirin combination treatment, have been launched in different countries given their significantly higher success rates.

Pegylated interferon alfa and ribavirin: This is still being used as first-line therapy choice for HCV patients with genotypes 2,3,4,5 and 6. It's also being used to treat HCV genotype 1 patients in countries where the new protease inhibitors have not been approved yet or where decisions on how to commission the drugs have not been taken yet.

Pegylated interferon alfa and ribavirin cures approximately half of all hepatitis C patients. A patient is considered to be cured if there's no virus in the blood six months after the end of treatment. This is different from hepatitis B therapy, which controls rather than cures the infection. Interferon comes in a syringe and ribavirin is available in pills.

The treatment may have side effects such as fatigue, flu-like symptoms, depression, hair and skin problems, and changes in blood chemistry. Therefore, treatment should be monitored by an experienced doctor or clinic. The duration of treatment is different from patient to patient. You usually need 24-48 weeks of treatment, but in some cases, 72 weeks may be recommended.

There are several subtypes of the hepatitis C virus, called genotypes. They don't seem to influence the course of the disease, but they respond differently to treatment. Patients infected with genotypes 1, 4, 5 and 6 are more difficult to cure than those infected with genotypes 2 and 3.

There are a number of new hepatitis C treatments in development.OURCE: World Hepatitis Alliance

(WhatDoctorsKnow is a magazine devoted to up-to-the minute information on health issues from physicians, major hospitals and clinics, universities and health care agencies across the U.S. Online at http://www.whatdoctorsknow.com.)

(c) 2013 WHATDOCTORSKNOW.COM DISTRIBUTED BY TRIBUNE CONTENT AGENCY, LLC.

Source

Gilead’s Single Tablet HIV Regimen Stribild® Demonstrates Durable Viral Suppression Through Three Years of Therapy

-- Long-Term Data In Treatment-Naïve Patients Highlight Stribild’s Sustained Efficacy, Safety and Tolerability Profile --

BRUSSELS--(BUSINESS WIRE)--Oct. 16, 2013-- Gilead Sciences, Inc. (Nasdaq: GILD) today announced three-year (144-week) efficacy and safety results from two pivotal Phase 3 studies (Studies 102 and 103) evaluating the once-daily single tablet regimen Stribild^® (elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) among treatment-naïve patients with HIV-1 infection. Data show that after three years of treatment, Stribild demonstrated comparable efficacy to two standard-of-care HIV regimens, Atripla^® (efavirenz 600 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) in Study 102 and a protease inhibitor-based regimen of ritonavir-boosted atazanavir plus Truvada^® (emtricitabine and tenofovir disoproxil fumarate) in Study 103. These data are being presented this week at the 14th European AIDS Clinical Society Conference (EACS) in Brussels, Belgium.

“HIV has become a chronic disease that can be managed with life-long therapy, increasing the need for convenient, once-daily treatment options that offer long-term efficacy and tolerability,” said Jürgen Rockstroh, MD, Professor of Medicine, University of Bonn, Germany. “In these large-scale clinical trials, Stribild demonstrated high and durable viral suppression and a favorable safety profile over three years of therapy. These results support Stribild as an important single-tablet treatment option for people starting antiretroviral therapy.”

Study 102 found that, at 144 weeks of treatment, 80 percent of Stribild patients (n=279/348) compared to 75 percent of patients receiving Atripla (n=265/352) achieved HIV RNA (viral load) less than 50 copies/mL based on the FDA snapshot algorithm (95 percent CI for the difference: -1.3 to 11.1 percent for Stribild vs. Atripla).

Similarly, in Study 103, 78 percent of Stribild patients (n=274/353) versus 75 percent of patients taking a protease inhibitor-based regimen of ritonavir-boosted atazanavir plus Truvada (n=265/355) achieved HIV RNA less than 50 copies/mL (95 percent CI for the difference: -3.2 to 9.4 percent for Stribild vs. the atazanavir-based regimen).

In both studies, rates of discontinuation due to adverse events were similar across all treatment groups (6 percent for Stribild in each study, 8 percent for Atripla and 9 percent for the atazanavir-based regimen).

In Study 102, the most common adverse events occurring in at least 10 percent of Stribild patients were diarrhea, nausea and upper respiratory tract infection, and for Atripla, they were abnormal dreams, dizziness and diarrhea. Stribild was associated with numerically lower rates of certain neuropsychiatric side effects compared to Atripla through 144 weeks, including abnormal dreams (16 percent for Stribild vs. 29 percent for Atripla), dizziness (8 percent vs. 26 percent) and insomnia (12 percent vs. 17 percent). The frequency of laboratory abnormalities was comparable between study regimens. Patients taking Stribild also experienced significantly lower increases in total cholesterol and LDL (low-density lipoprotein, or “bad” cholesterol) compared to patients taking Atripla.

In Study 103, Grade 3-4 laboratory abnormalities were generally similar for both treatment regimens, with the exception of hyperbilirubinemia, the rate of which was lower among patients taking Stribild compared to those taking the atazanavir-based regimen through 144 weeks of treatment (2 percent vs. 69 percent). In addition, patients taking Stribild in Study 103 experienced a lower change from baseline in spine bone mineral density compared to atazanavir patients (-1.43 percent vs. -3.68 percent , p=0.018), and a similar median change from baseline in hip bone mineral density (-2.83 percent for Stribild and -3.77 percent for the atazanavir-based regimen, p=0.23).

Stribild has a Boxed Warning on the risks of lactic acidosis/severe hepatomegaly with steatosis and post treatment acute exacerbation of hepatitis B; see below for important safety information.

Stribild was approved by the U.S. Food and Drug Administration in August 2012 and by the European Commission in May 2013.

Study 102

Study 102 is a randomized (1:1), double-blind Phase 3 clinical trial comparing the efficacy, safety and tolerability of Stribild (n=348) versus Atripla (n=352) among HIV-infected treatment-naïve adults with HIV RNA levels greater than or equal to 5,000 copies/mL. The primary endpoint of the study is the proportion of patients achieving HIV RNA levels less than 50 copies/mL at 48 weeks of treatment, per the FDA snapshot algorithm. Secondary objectives are to evaluate the efficacy, safety and tolerability of the treatment regimens through 192 weeks of treatment.

At baseline, patients in the Stribild arm had a median HIV RNA of 4.75 log₁₀ copies/mL and mean CD4 cell count of 391 cells/mm³. Patients in the Atripla arm had a median HIV RNA of 4.78 log₁₀ copies/mL and mean CD4 cell count of 382 cells/mm³. Thirty-four percent of Stribild patients and 33 percent of Atripla patients had HIV RNA greater than 100,000 copies/mL. Twelve percent of Stribild patients and 14 percent of Atripla patients had CD4 counts less than or equal to 200 cells/mm³.

Mean increases in CD4 cell counts were 321 cells/mm³ for Stribild patients and 300 cells/mm³ for Atripla patients at 144 weeks. Virologic failure rates were seven percent for Stribild and 10 percent for Atripla based on a component of the FDA snapshot analysis.

Through 144 weeks, six percent of Stribild patients and eight percent of Atripla patients discontinued treatment due to adverse events. Adverse events leading to treatment discontinuation among patients taking Stribild were renal events (2.3 percent), depression (0.3 percent) and fatigue (0.3 percent), and among patients taking Atripla, they were depression (1.4 percent), rash events and drug hypersensitivity (1.4 percent), fatigue (0.6 percent), abnormal dreams (0.6 percent), insomnia (0.6 percent) and anxiety (0.6 percent).

The frequency of Grade 3-4 adverse events and laboratory abnormalities was comparable between study regimens. Median changes from baseline in total cholesterol and LDL at 144 weeks were significantly smaller for Stribild compared to Atripla and were, respectively, +14 and +13 mg/dL for Stribild and +22 and +19 mg/dL for Atripla (total cholesterol, p=0.007; LDL, p=0.007). Median changes from baseline in HDL (high-density lipoprotein or “good” cholesterol) and triglycerides were similar for both treatment arms and were, respectively, +7 mg/dL and +9 mg/dL for Stribild and +9 mg/dL and +5 mg/dL for Atripla (HDL, p=0.021; triglycerides, p=0.72).

Median increases from baseline to 144 weeks in serum creatinine were 0.14 mg/dL for Stribild and 0.01 mg/dL for Atripla. There were four cases of proximal renal tubulopathy among Stribild patients reported in the first 48 weeks and none between weeks 48 and 144 weeks. Between 96 and 144 weeks of treatment, one Stribild patient discontinued treatment due to an isolated rise in creatinine without features of proximal renal tubulopathy, and the patient improved after treatment discontinuation.

There were no cases of resistance observed with Stribild between weeks 96 and 144.

Study 103

Study 103 is a randomized (1:1), double-blind Phase 3 clinical trial comparing the efficacy, safety and tolerability of Stribild (n=353) versus atazanavir 300 mg boosted by ritonavir 100 mg plus Truvada (n=355) among HIV-infected treatment-naïve adults with baseline HIV RNA levels greater than 5,000 copies/mL. The primary endpoint of the study is the proportion of patients achieving HIV RNA levels less than 50 copies/mL at 48 weeks of treatment, per the FDA snapshot algorithm. Secondary objectives are to evaluate the efficacy, safety and tolerability of the treatment regimens through 192 weeks of treatment.

At baseline, patients in the Stribild arm had a median HIV RNA of 4.88 log₁₀ copies/mL and mean CD4 cell count of 364 cells/mm³. Patients in the atazanavir-based arm had a median HIV RNA of 4.86 log₁₀ copies/mL and mean CD4 cell count of 375 cells/mm³. Forty-two percent of Stribild patients and 40 percent of atazanavir patients had HIV RNA greater than 100,000 copies/mL. Fifteen percent of Stribild patients and 11 percent of atazanavir patients had CD4 counts less than or equal to 200 cells/mm³.

Patients in the Stribild arm experienced a mean increase of 280 cells/mm³ in CD4 cell count at 144 weeks and patients on the atazanavir-based regimen had a mean increase of 293 cells/mm³. Virologic failure rates were eight percent for Stribild and seven percent for the atazanavir-based regimen based on a component of the FDA snapshot analysis.

Through 144 weeks, six percent of Stribild patients and nine percent of patients on the atazanavir-based regimen discontinued treatment due to adverse events. Adverse events leading to treatment discontinuation among patients taking Stribild were renal events (1.4 percent), hepatitis C (0.6 percent), diarrhea (0.6 percent), pyrexia (0.6 percent), nausea (0.3 percent), vomiting (0.3 percent) and fatigue (0.3 percent). The most common adverse events leading to treatment discontinuation among patients taking the atazanavir-based regimen were renal events (2.3 percent), nausea (1.1 percent), ocular icterus (1.1 percent), vomiting (0.6 percent), fatigue (0.6 percent), jaundice (0.6 percent), dizziness (0.6 percent), drug eruption (0.6 percent), hepatitis C (0.3 percent), diarrhea (0.3 percent) and pyrexia (0.3 percent). The most common adverse events occurring in at least 10 percent of patients in either treatment arm were diarrhea, nausea and upper respiratory tract infection.

With the exception of hyperbilirubenemia among atazanavir patients, Grade 3-4 laboratory abnormalities were similar for both treatment regimens. Median changes from baseline in total cholesterol, HDL and LDL at 144 weeks were similar for Stribild and the atazanavir-based regimen and were, respectively, +20, +8 and +17 mg/dL for Stribild, and +16, +7 and +18 mg/dL for the atazanavir-based regimen (total cholesterol, p=0.30; HDL, p=0.39; LDL, p=0.98). The median change in triglycerides was +15 mg/dL for Stribild and +22 mg/dL for the atazanavir-based regimen (p=0.24).

Both regimens had comparable renal profiles, with median increases from baseline to 144 weeks in serum creatinine of 0.12 mg/dL for Stribild and 0.08 mg/dL for the atazanavir-based regimen. Through 144 weeks, no patients taking Stribild and three patients taking the atazanavir-based regimen discontinued treatment due to proximal renal tubulopathy. Between 96 and 144 weeks of treatment, two Stribild patients and one atazanavir patient discontinued treatment due to an isolated rise in creatinine without features of proximal renal tubulopathy.

There were two cases of resistance observed in both the Stribild and atazanavir-based arms between weeks 96 and 144.

Studies 102 and 103 are ongoing in a blinded fashion. After week 192, patients will continue to take their blinded study drug until treatment assignments have been unblinded. Additional information about the study can be found at www.clinicaltrials.gov.

About Stribild

Stribild contains four Gilead compounds in a complete once-daily, single tablet regimen: elvitegravir 150 mg; cobicistat 150 mg; emtricitabine 200 mg; and tenofovir disoproxil fumarate 300 mg. Stribild is indicated in the United States as a complete regimen for the treatment of HIV-1 infection in adults who are antiretroviral treatment-naïve. Stribild does not cure HIV-1 infection.

Elvitegravir is a member of the integrase inhibitor class of antiretroviral compounds. Integrase inhibitors interfere with HIV replication by blocking the ability of the virus to integrate into the genetic material of human cells. Elvitegravir was licensed by Gilead from Japan Tobacco Inc. (JT) in March 2005. Under the terms of Gilead’s agreement with JT, Gilead has exclusive rights to develop and commercialize elvitegravir in all countries of the world, excluding Japan, where JT retains rights.

Cobicistat is Gilead’s proprietary potent mechanism-based inhibitor of cytochrome P450 3A (CYP3A), an enzyme that metabolizes drugs in the body.

On September 25, 2013, cobicistat was approved by the European Commission under the tradename Tybost^®. On September 20, 2013, the Committee for Medicinal Products for Human Use, the scientific committee of the European Medicines Agency, adopted a positive opinion on Gilead’s Marketing Authorisation Application (MAA) for elvitegravir.

Elvitegravir as a standalone agent and cobicistat as a standalone agent in the United States are investigational products and their safety and efficacy have not been established.

IMPORTANT SAFETY INFORMATION

BOXED WARNING: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B

• Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir disoproxil fumarate (tenofovir DF), a component of Stribild, in combination with other antiretrovirals.
• Stribild is not approved for the treatment of chronic hepatitis B virus (HBV) infection and the safety and efficacy of Stribild have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued emtricitabine or tenofovir DF, components of Stribild. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue Stribild. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

Contraindications

• Coadministration: Do not use with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. Do not use with drugs that strongly induce CYP3A as this may lead to loss of efficacy and possible resistance to Stribild. Use with the following drugs is contraindicated: alfuzosin, rifampin, dihydroergotamine, ergotamine, methylergonovine, cisapride, lovastatin, simvastatin, pimozide, sildenafil for pulmonary arterial hypertension, triazolam, oral midazolam, and St. John’s wort.

Warnings and precautions

• New onset or worsening renal impairment: Cases of acute renal failure and Fanconi syndrome have been reported with the use of tenofovir DF and Stribild. Monitor estimated creatinine clearance (CrCl), urine glucose, and urine protein in all patients prior to initiating and during therapy; additionally monitor serum phosphorus in patients with or at risk for renal impairment. Cobicistat may cause modest increases in serum creatinine and modest declines in CrCl without affecting renal glomerular function; patients with an increase in serum creatinine >0.4 mg/dL from baseline should be closely monitored for renal safety. Do not initiate Stribild in patients with CrCl below 70 mL/min. Discontinue Stribild if CrCl declines below 50 mL/min. Avoid concurrent or recent use with a nephrotoxic agent.
• Other antiretroviral products: Stribild is a complete regimen for the treatment of HIV-1 infection. Do not coadminister with other antiretroviral products, including products containing any of the same active components; products containing lamivudine; products containing ritonavir; or with adefovir dipivoxil.
• Decreases in bone mineral density (BMD) and cases of osteomalacia have been seen in patients treated with tenofovir DF. Consider monitoring BMD in patients with a history of pathologic fracture or risk factors for bone loss.
• Fat redistribution and accumulation have been observed in patients receiving antiretroviral therapy.
• Immune reconstitution syndrome, including the occurrence of autoimmune disorders with variable time to onset, has been reported.

Adverse reactions

• Common adverse drug reactions in clinical studies (incidence ≥5%; all grades) were nausea (16%), diarrhea (12%), abnormal dreams (9%), and headache (7%).

Drug interactions

• CYP3A substrates: Stribild can alter the concentration of drugs metabolized by CYP3A or CYP2D6. Do not use with drugs highly dependent on these factors for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening adverse events.
• CYP3A inducers: Drugs that induce CYP3A can decrease the concentrations of components of Stribild. Do not use with drugs that strongly induce CYP3A as this may lead to loss of virologic response and possible resistance to Stribild.
• Drugs affecting renal function: Coadministration of Stribild with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of emtricitabine and tenofovir and the risk of adverse reactions.
• Antacids: Separate Stribild and antacid administration by at least 2 hours.
• Prescribing information: Consult the full prescribing information for Stribild for more information on potentially significant drug interactions, including clinical comments.

Dosage and administration

• Adult dosage: One tablet taken orally once daily with food.
• Renal impairment: Do not initiate in patients with CrCl below 70 mL/min. Discontinue in patients with CrCl below 50 mL/min.
• Hepatic impairment: Not recommended in patients with severe hepatic impairment.
• Testing prior to initiation: Test patients for HBV infection and document baseline CrCl, urine glucose, and urine protein.

Pregnancy and breastfeeding

• Pregnancy Category B: There are no adequate and well-controlled studies in pregnant women. Use during pregnancy only if the potential benefit justifies the potential risk. An Antiretroviral Pregnancy Registry has been established.
• Breastfeeding: Emtricitabine and tenofovir have been detected in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed.

About Gilead Sciences

Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company’s mission is to advance the care of patients suffering from life-threatening diseases worldwide. Headquartered in Foster City, California, Gilead has operations in North America, Europe and Asia Pacific.

Forward-Looking Statement

This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including the risk that healthcare providers may not recognize the benefits of Stribild. In addition, as Stribild is used over longer periods of time by many patients with underlying health problems taking numerous other medicines, Gilead may find new issues such as safety, resistance or drug interaction issues, which may require it to provide additional warnings or contraindications on the label or narrow Stribild’s approved indication, each of which could reduce the market acceptance of Stribild. In addition, regulatory authorities including in the European Union may not approve our marketing application for elvitegravir, and the FDA may not approve marketing applications for elvitegravir and/or cobicistat. Further, even if marketing approval is granted for any of these products, there may be significant limitations on their use. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. The reader is cautioned not to rely on these forward-looking statements. These and other risks are described in detail in Gilead’s Quarterly Report on Form 10-Q for the quarter ended June 30, 2013, as filed with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation to update any such forward-looking statements.

U.S. full prescribing information for Stribild, Atripla, and Truvada is available at www.gilead.com.

EU Summary of Product Characteristics for Stribild, Atripla and Truvada is available at www.ema.europa.eu

Stribild and Truvada are registered trademarks of Gilead Sciences, Inc.

Atripla is a registered trademark of Bristol-Myers Squibb & Gilead Sciences, LLC.

For more information on Gilead Sciences, please visit the company’s website at www.gilead.com, follow Gilead on Twitter (@GileadSciences) or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.

Source: Gilead Sciences, Inc.

Gilead Sciences, Inc.
Patrick O’Brien, 650-522-1936 (Investors)
Cara Miller, 650-522-1616 (Media, U.S.)
Stephen Head, +44 208-587-2359 (Media, Europe)

Source

Treating Hepatitis C Infection Following Liver Transplantation with Telaprevir and Boceprevir

Accepted Manuscript

Editorial

Victory and Defeat at Heraclea - Treating Hepatitis C Infection Following Liver Transplantation with Telaprevir and Boceprevir

Michael Charlton, Travis Dick

PII: S0168-8278(13)00696-X

DOI: http://dx.doi.org/10.1016/j.jhep.2013.10.006

Reference: JHEPAT 4894

To appear in: Journal of Hepatology

Received Date: 30 September 2013

Accepted Date: 3 October 2013

Please cite this article as: Charlton, M., Dick, T., Victory and Defeat at Heraclea - Treating Hepatitis C Infection Following Liver Transplantation with Telaprevir and Boceprevir, Journal of Hepatology (2013), doi: http:// dx.doi.org/10.1016/j.jhep.2013.10.006

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Introduction

Although possibly having peaked, HCV associated liver disease continues to be the most common indication for liver transplantation in the West. Although the impact of HCV infection varies substantially between recipients, allograft failure secondary to recurrence of HCV infection is the most frequent cause of death and graft failure in HCV infected recipients.

Attenuating the impact of HCV on posttransplant patient and graft survival has been a critical priority for transplant physicians and their patients. In this edition of the Journal of Hepatology Duclos-Vallée et al., report the results of a multicenter study of 37 liver transplant recipients (male: 92%, age 57±11years), who were treated with PEG interferon, ribavirin and boceprevir (n=18) or telaprevir (n=19) for recurrence of HCV infection following liver transplantation. The indication for therapy was progressive HCV recurrence (fibrosis stage ≥F2 (83%) or fibrosing cholestatic hepatitis (16%)). Eighteen patients were treatment-naive, five were relapsers and 14 were non-responders to prior dual therapy after LT. The patient population was, by and large, typical of recipients with post-LT HCV infection who are considered for boceprevir and telaprevir based antiviral therapy. The main finding of the study by Duclos-Vallée et al., is that a sustained virological response (SVR) at 12 weeks after treatment discontinuation was observed in 20% and 71% of patients in the telaprevir (TVR) and boceprevir (BOC) groups, respectively, for an overall SVR rate of 50%. While a study with an n of 37 may seem unimportant, to dismiss the results of this study would be to miss an opportunity to gain insights into the opportunities and challenges of treating posttransplant HCV infection. The report by Duclos-Vallée et al., which is thoughtful in design and presentation, is not without limitations, including small sample size, lack of randomization and absence of a prospective antiviral treatment protocol. To focus on the shortcomings would, however, be a disservice to the field and the authors. There are important lessons to be had. The first and most obvious lessons are that boceprevir and telaprevir are neither particularly effective nor safe in this patient population. While the authors focus on the “encouraging” complete early virological response rate (cEVR) of 73%, when it comes to treating HCV, particularly following liver transplantation, SVR is king. The observed SVR rate of 50% may be viewed as somewhat less encouraging than the cEVR rate. The benefit of treatment that may theoretically eventually be reaped by those recipients who achieved SVR needs to weighed against the cost of boceprevir and telaprevir based antiviral therapy. Three patients (8%) died on treatment. With only 28 (of 37) patients reaching the combined endpoints of end of treatment / death / treatment discontinued, nine patients are still on treatment. Plenty of opportunity for participants to die and experience non-lethal adverse events thus remains.

The non-lethal adverse events are of particular interest. Deterioration in renal function was common, with 5 (14%) of the patients who survived antiviral treatment developing patients developing renal failure, with a mean decline in GFR of 3.8mls/min during treatment. As renal function is one of the best predictors of longterm outcomes, the negative impact of antiviral therapy may continue well beyond the end of antiviral treatment. Add in one third of patients getting hospitalized for sundry other adverse events and one third requiring blood transfusions and the net benefit is not completely obvious. Only half of five year posttransplant mortality/graft loss is due to HCV recurrence. Overall five year survival rates for recipients with HCV infection are ~70% and the risk of mortality related specifically to HCV recurrence is 15% by the fifth postoperative year.1 A 100% SVR could thus reduce 5 year post-LT mortality by 15%. With an observed mortality rate related to antiviral treatment in the study by Duclos-Vallée et al., of 8%, the best case net benefit is a 7% reduction in five year mortality attributable to antiviral therapy. As two thirds of those with the most severe recurrence of HCV did not respond to antiviral therapy in this study, it is entirely plausible that there will be no net survival benefit to treating liver transplant recipients with BOC or TVR in the medium term (the likelihood of mortality/graft loss due to HCV is likely to highest among the FCH/cirrhosis patients, who had a low SVR rate). The frequency of SAEs greatly limited the potential efficacy posttransplant antiviral therapy in the study by Duclos-Vallée et al., with only half of the ~50% of patients who discontinued treatment doing so for virological nonresponsiveness/breakthrough, the remainder dying or experiencing adverse events severe enough to stop antiviral treatment. A third lesson of the study by Duclos-Vallée et al., is that full realization of the potential benefit of BOC and TVR based posttransplant antiviral therapy requires minimisation of the side effects of these agents and those of peginterferon and ribavirin. The high frequency of infections and renal insufficiency suggests overexposure to calcineurin inhibitors. This is despite effective CNI trough level management through dose adjustments in anticipation of in response to the introduction of the cytochrome P450 inhibitors boceprevir and telaprevir. Renal insufficiency and life threatening infections despite stable CNI levels is a consistent emerging theme of posttransplant antiviral therapy. A thorough appreciation of the impact of post-LT antiviral therapy on the pharmacokinetics of immunosuppression is essential to achieving optimal safety and efficacy.

The cytochrome P450 (CYP) enzyme system is responsible for drug metabolism via oxidation in the liver and intestines allowing drugs to be eliminated into the bile or urine. The CYP 3A4 isoenzyme is used by more than 50% of approved medications for elimination from the body.1 Protease inhibitors, such as boceprevir (BOC) and telaprevir (TVR) in addition to being potent inhibitors of the CYP 3A4 enzyme leading to many potential drug-drug interactions (DDI), are also (TVR > BOC) inhibitors of P-gp, the active transport enzyme, p-glycoprotein (P- gp). P-gp is an efflux pump that ultimately inhibits intestinal absorption of medications from the gastrointestinal tract. Inhibition of P-gp can increase concentrations of drugs that would typically be blocked from absorption into the blood stream. Examples of medications that will be increased during coadministration of TVR via P-gp inhibition are morphine,2 digoxin3 and midazolam.3 (Table) The onset of CYP 3A4 inhibition is typically within the first couple of days of protease inhibitor therapy. BOC and TVR exhibit mechanism-based inhibition of CYP 3A4 meaning that the isoenzyme is inhibited for its life until new CYP 3A4 protein can be synthesized. The corollary is that resolution of CYP 3A4 inhibition may be delayed after discontinuing protease inhibitor therapy. Empiric dose adjustments, judicious monitoring of co- administered drugs, and screening for potential adverse effects are warranted during and after BOC and TVR initiation and discontinuation.

Most available data for drug-drug interactions (DDI) with these protease inhibitors are in healthy volunteers with normal hepatic function. As HCV can decrease CYP function, increasing calcineurin inhibitor concentrations approximately 30%,4,5 pharmacokinetic effects in LT recipients with HCV infection may be more pronounced than tose seen ion healthy volunteers. Tacrolimus doses as little as 0.5mg per week are adequate to maintain therapeutic concentrations when given with the protease inhibitor combination of lopinivir/ritonavir.6 In healthy volunteers TVR can increase tacrolimus concentrations as much as 70-fold and cyclosporine concentrations 4.6-fold,7 while BOC increases tacrolimus concentrations 17-fold and cyclosporine 2.7 fold.8 Based on the known effects of BOC and TVR, CNI and mTOR doses must be decreased empirically when starting protease inhibitor therapy and consequently increased when protease inhibitor therapy is discontinued. Sirolimus, and everolimus are also known substrates of CYP 3A4 and P-gp. No published data exist describing the DDI between everolimus and TVR, however everolimus clearance is decreased 52% when administered with BOC.9 As sirolimus carries a black box warning for use in liver transplantation,10 its may be wise to avoid this agent altogether in pateints receving TVR or BOC. Consideration might be given to everolimus use in place of sirolimus if an mTOR inhibitor is indicated. The shorter half-life of everolimus may make management of drug-drug interactions easier than sirolimus.

DDI can be significant in transplant recipients as the calcineurin inhibitors, mTOR inhibitors, and a multitude of other medications are transported by P-gp and/or metabolized by the CYP 3A4 enzyme. It is important to screen concomitantly adminsterd medications other than the CNIs and mTORs for potential DDI or contraindications. Common CYP 3A4 substrates include azole antifungal agents, HMG-Co-A reductase inhibitors (statins), methadone, and many others. Increasing the frequency of therapeutic drug monitoring of immunosuppressants and other concomitant medications is imperative when both starting and stopping protease inhibitors.

Finally, as all CNI trough levels are measured in whole blood, trough levels will not accurately reflect the biologically active (immunosuppressive and nephrotoxic) free CNI trough levels. The major portion of whole blood CsA and TAC is sequestered in erythrocytes, with hematocrit known to be inversely related to plasma concentrations of CNIs.11 Due to RBV induced hemolysis a shift of the erythrocyte-bound CsA fraction to plasma will occur. Anemia will be exacerbated by peginterferon and BOC induced bone marrow suppression. In the context of progressive, ubiquitous and frequently severe anemia relying on whole blood level monitoring may not be safe. As free CNI level monitoring is not widely available, consideration should be given to adjusting target CNI trough levels downward in the context of a falling hematocrit.

On being congratulated for his victory over the Romans at Heraclea, whose army suffered irrecoverable casualties, King Pyrrhus replied that one more such victory would utterly undo him. The report by Duclos-Vallée et al., should serve to remind us of the possibly Pyrrhic nature of our battle with posttransplant HCV infection. We eagerly await the advent of HCV therapies that are more effective and more easily tolerated than those that incorporate BOC and TVR. For patients with mild recurrence, waiting may be more prudent than joining the battle at Heraclea.

References

1. Charlton M, Seaberg E. Impact of immunosuppression and acute rejection on recurrence of hepatitis C: results of the National Institute of Diabetes and Digestive and Kidney Diseases Liver Transplantation Database. Liver Transplantation & Surgery 1999;5:107- 114.

2. Fudin J, Fontenelle DV, Fudin HR, Carlyn C, Hinden DA, Ashley CC. Potential p- glycoprotein pharmacokinetic interaction of telaprevir with morphine or methadone. Journal of Pain & Palliative Care Pharmacotherapy 2013;27:261-267.

3. Garg V, Chandorkar G, Farmer HF, Smith F, Alves K, van Heeswijk RP. Effect of telaprevir on the pharmacokinetics of midazolam and digoxin. J Clin Pharmacol 2012;52:1566-1573.

4. Oo YH, Dudley T, Nightingale P, Haydon G, Mutimer D. Tacrolimus and cyclosporine doses and blood levels in hepatitis C and alcoholic liver disease patients after liver transplantation. Liver Transpl 2008;14:81-87.

5. Kugelmas M, Osgood MJ, Trotter JF, Bak T, Wachs M, Forman L, et al. Hepatitis c virus therapy, hepatocyte drug metabolism, and risk for acute cellular rejection. Liver Transpl 2003;9:1159-1165.

6. Jain AB, Venkataramanan R, Eghtesad B, Marcos A, Ragni M, Shapiro R, et al. Effect of coadministered lopinavir and ritonavir (Kaletra) on tacrolimus blood concentration in liver transplantation patients. Liver Transpl 2003;9:954-960.

7. Garg V. van Heeswijk R, Lee JE, Alves K, Nadkarni P, Luo X. Effect of telaprevir on the pharmacokinetics of cyclosporine and tacrolimus. Hepatology 2011;54:20-27.

8. Hulskotte E, Gupta S, Xuan F, van Zutven M, O’Mara E, Feng HP, et al. Pharmacokinetic interaction between the hepatitis c virus protease inhibitor boceprevir and cyclosporine and tacrolimus in healthy volunteers. Hepatology 2012;56:1622-1630.

9. Coilly A, Furlan V, Roche B, Barau C, Noel C, Bonhomme-Faivre L, et al. Practical management of boceprevir and immunosuppressive therapy in liver transplant recipients with hepatitis c recurrence. Antimicrob Agents Chemother 2012;56:5728-34.

10. O’Leary J, McKenna GJ, Klintmalm GB, Davis GL. Effect of telaprevir on the pharmacokinetics of sirolimus in liver transplant recipients. Liver Transpl 2013;19:463- 465.

11. Akhlaghi F, Trull AK. Distribution of cyclosporin in organ transplant recipients. Clin Pharmacokinet 2002;41(9):615-637.

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