Tuesday, June 3, 2014

NCKU team discovers pathogenesis of liver fibrosis and developed antibodies that reduce liver damage

NCKU team discovers new  liver disease treatment
The China Post news staff
June 4, 2014, 12:00 am TWN

TAIPEI, Taiwan -- A National Cheng Kung University (NCKU) team has discovered the pathogenesis of liver fibrosis and developed antibodies that reduce liver damage, inhibit hepatic fibrosis and recover liver function, according to a press release from the school. Ming-shi Chang, chair professor of biochemistry and molecular biology at NCKU, led the team to make another breakthrough in their research on interleukin 20 (IL-20), said the NCKU.

Currently, NCKU has been granted a patent in the United States, which has attracted great interest from the biotechnology industry, the university said.

Hepatitis, fatty liver disease, and hepatotoxicity are some of the primary disorders that lead to the development of liver diseases, according to Chang, who added that inflammation of the liver can evolve into liver fibrosis and cirrhosis, and patients in the final stages of liver cirrhosis often develop liver cancer.

Inflammation is the source of many diseases, said Chang. She also said that IL-20 is involved in several inflammatory diseases.

Chang's team discovered that IL-20 is a primary cause of liver diseases, and they confirmed that the liver tissue of patients with liver fibrosis, liver cirrhosis and liver cancer have significantly higher levels of IL-20. IL-20 causes liver inflammation and increases the development of the extracellular matrix, thus causing liver fibrosis and cirrhosis, the NCKU stated.

IL-20 is a protein secreted by the human immune system, Chang said. An excessive amount of IL-20 can damage body tissue and, therefore, lead to many diseases such as osteoporosis and a variety of liver diseases, said the NCKU.

Most liver diseases result from liver damage caused by long-term chronic hepatitis. Patients with liver disease include people infected with the hepatitis B and C viruses, as well as alcoholic hepatitis and toxin-induced hepatitis.

Repeated or prolonged chronic hepatitis can seriously damage liver cells. This damage stimulates fibroblasts in the liver to produce collagen fibers, which are then deposited in the liver and fill up the empty spaces left by dead hepatocytes. Finally, this fibrosis causes liver cirrhosis, the NCKU stated.

Chang and her research team observed that patients with liver fibrosis, liver cirrhosis and liver cancer also had high levels of IL-20. After investigating this phenomenon, they discovered that IL-20 activates hepatic stellate cells and stimulates transforming growth factor (TGF)-beta1, tumor necrosis factor (TNF)-alpha as well as Type I Collagen in these cells to increase the accumulation of the extracellular matrix.

Because IL-20 is a protein secreted by the human body, Chang and her research team developed an anti-IL-20 monoclonal antibody, which inhibits the functions of IL-20 and stops IL-20-induced liver damage at the same time.

Chang's research has provided a solution to the therapeutic management of liver fibrosis and a new direction for treating liver diseases, said the NCKU.

Their research titled “IL-20 and IL-20R1 antibodies protect against liver fibrosis” has been published in the May issue of Hepatology.

Also See:
2014 Apr 25. doi: 10.1002/hep.27189. [Epub ahead of print]

IL-20 and IL-20R1 antibodies protect against liver fibrosis.

  • 1Institute of Biopharmaceutical Sciences, National Cheng Kung University, Tainan, Taiwan.
Interleukin (IL)-20 is a proinflammatory cytokine of the IL-10 family and involved in rheumatoid arthritis, atherosclerosis, stroke, and osteoporosis. However, the pathophysiological roles of IL-20 in liver injury have not been extensively studied. We explored the involvement of IL-20 in liver injury and the therapeutic potential of IL-20 antagonists for treating liver fibrosis. Compared with the normal liver tissue from healthy individuals, the amount of IL-20 was much higher in hepatocytes and hepatic stellate cells in liver biopsies from patients with fibrosis, cirrhosis, and hepatocellular carcinoma. Carbon tetrachloride (CCl4 ) treatment induced IL-20 that further upregulated the expression of transforming growth factor (TGF)-β1 and p21WAF1 and resulted in cell cycle arrest in the Clone-9 rat hepatocyte cell line. IL-20 activated quiescent rat hepatic stellate cells (HSCs) and upregulated TGF- β1 expression. IL-20 also increased TGF- β1, tumor necrosis factor (TNF)-α, and type I collagen (Col-I) expression, and promoted the proliferation and migration of activated HSCs. Serum IL-20 was significantly elevated in mice with short-term and long-term CCl4 -induced liver injury. In mice with short-term liver injury, anti-IL-20 monoclonal antibody (7E) and anti-IL-20 receptor (IL-20R1) monoclonal antibody (51D) attenuated hepatocyte damage caused by CCl4 , TGF- β1, and chemokine production. In mice with long-term liver injury, 7E and 51D inhibited CCl4 -induced cell damage, TGF- β1 production, liver fibrosis, HSC activation, and extracellular matrix (ECM) accumulation, which was caused by the reduced expression of tissue inhibitors of metalloproteinases (TIMPs) as well as increased metalloproteinase (MMP) expression and Col-I production. IL-20R1-deficient mice were protected from short-term and long-term liver injury. Conclusion: We identified a pivotal role of IL-20 in liver injury and showed that 7E and 51D may be therapeutics for liver fibrosis. (Hepatology 2014;).
Copyright © 2014 American Association for the Study of Liver Diseases.

Cytokines; hepatic stellate cell; hepatocyte; inflammation; liver injury

Quebec Becomes First Province to Reimburse Sovaldi® for the Treatment of Chronic Hepatitis C

Quebec Becomes First Province to Reimburse Sovaldi® for the Treatment of Chronic Hepatitis C

~ Priority Review by INESSS Provides Recommendation to Treat Patients with Genotypes 1 and 4 HCV Infection Regardless of Fibrosis Level ~

MONTREAL, June 2, 2014 /CNW/ - Gilead Sciences Canada, Inc. is pleased to announce that the Health and Social Services Ministry has placed Sovaldi® (sofosbuvir), the newest treatment for chronic hepatitis C virus (HCV) infection approved for sale in Canada, on the Liste de médicaments (effective June 2, 2014). With this listing, Quebec becomes the first Canadian province to provide access to Sovaldi for treatment-naïve patients with genotypes 1 and 4 HCV infection regardless of liver severity.

The listing follows a Priority Review and evaluation by the Institut national d'excellence en santé et en services sociaux (INESSS) that concluded Sovaldi provides therapeutic and clinical value, is cost effective, is well tolerated, and offers important societal benefits for the broader population. INESSS reported several advantages of Sovaldi, including its short treatment duration (12 weeks), positive side effect profile (anemia and rashes), and administration of one pill once a day (with pegylated interferon and ribavirin) without the need for a specific diet. In addition, INESSS stated that Sovaldi fulfills a significant healthcare need in the treatment of genotype 4, as until now, only a combination of pegylated interferon and ribavirin had been used.1

A recent analysis, "Health Care Resources Utilization in Hepatitis C Virus Infection and Cost Associated with Adverse Events: An Analysis of the Quebec Provincial Drug Reimbursement Program Database", noted that treatment with previous therapies resulted in lower treatment completion and cure rates than treatment with Sovaldi. In addition, previous therapies resulted in significant anemia management costs per patient.2

"Treatment with newer therapies at any stage of infection, with fewer side effects, is a goal that is both achievable and cost effective," said Dr. Marc Bilodeau, Associate Professor of Medicine, Université de Montréal, and a co-author of the article. "By intervening early, we can prevent progression to more advanced stages of disease and the associated adverse outcomes."

Dr. Bilodeau added, "Quebec has recognized the health-system and societal benefits associated with newer hepatitis C treatment that improves upon the previous standard of care. As the first province to reimburse Sovaldi, Quebec has demonstrated its leadership in addressing this imminent public health issue and providing the opportunity for cure to more patients."

In the most recent issue of the Canadian Journal of Gastroenterology and Hepatology, the article, "Burden of disease and cost of chronic hepatitis C virus infection in Canada", reports that Canada will experience a significant increase in cases of advanced HCV-related liver disease over the next 20 years. Estimates include: an 89 per cent increase in cases of compensated cirrhosis (scarring of the liver with no loss of function); an 80 per cent increase in cases of decompensated cirrhosis (severe scarring of the liver with advanced symptoms and loss of function); a 205 per cent increase in cases of liver cancer, and a 160 per cent increase in cases of liver-related deaths.3

The article also states that associated health care costs will increase dramatically, mainly attributable to cirrhosis and its complications including liver cancer and liver transplantation. Authors estimate a 60 per cent increase in longer-term health care costs associated with HCV until its peak is reached in 2032 (not including antiviral therapy, virology testing and indirect medical costs).3

"We are pleased that Quebec has recognized the clinical value of Sovaldi as a curative therapy for treatment-naïve patients living with genotype 1 or 4 hepatitis C, regardless of their disease severity," said Edward Gudaitis, General Manager, Gilead Sciences Canada, Inc. "Gilead also welcomes the province's affirmation that Sovaldi is a cost-effective medicine that has the potential to reduce the burden of this disease on the health care system. We look forward to the outcome of additional reviews of Sovaldi that are being conducted by other provinces and territories in Canada."

About Sovaldi
Sovaldi is a once-daily direct-acting antiviral agent for the treatment of chronic hepatitis C infection. Sovaldi is indicated for use in genotypes 1 and 4 in combination with pegylated interferon and ribavirin, and in genotypes 2 and 3 in combination with ribavirin alone. In clinical studies, Sovaldi has achieved a cure rate of greater than 90 per cent after 12 weeks of treatment.

About Gilead Sciences
Gilead Sciences, Inc. 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 Sciences has operations in North and South America, Europe and Asia Pacific. Gilead Sciences Canada, Inc. is the Canadian affiliate of Gilead Sciences, Inc. and was established in Mississauga, Ontario in 2005.

1. Excerpt from Health and Social Services Ministry; Sovaldi in the treatment of chronic hepatitis C with genotypes 1 and 4.

2. "Health Care Resources Utilization in Hepatitis C Virus Infection and Cost Associated with Adverse Events: An Analysis of the Quebec Provincial Drug Reimbursement Program Database"; Lachine, J et al. Abstracts accepted at 2013 AASLD, 2013 ISPOR, and 2014 CDDW.

3. "Burden of disease and cost of chronic hepatitis C infection in Canada"; RP Myers, M Krajden, M Bilodeau, K Kaita, P Marotta, K Peltekian, A Ramji, C Estes, H Razavi, M Sherman; Canadian Journal of Gastroenterology and Hepatology, May 2014.

SOURCE Gilead Sciences, Inc. For further information: Cara Miller, Gilead Sciences, Inc., 1-650-522-1616

Gilead Hepatitis-C Drug Boost Seen on Medicare Test Plan

Gilead Hepatitis-C Drug Boost Seen on Medicare Test Plan

By Alex Wayne June 03, 2014

Medicare, the U.S. health plan for older Americans, will cover the cost of screening for hepatitis-C, a decision that may further open the government’s wallet for Gilead Sciences Inc. (GILD:US)’s $84,000 cure for the disease.

Adults at high risk for infection, including those who inject illegal drugs or had a blood transfusion before 1992, are eligible, as is anyone in Medicare age 49 to 69, the agency said in a memo today. A hepatitis-C diagnosis could lead to further use of Gilead’s Sovaldi, which costs $84,000 for a 12-week course of treatment and cures the disease.

While 2.7 million Americans may be infected with Hepatitis-C, health officials say many don’t know it since the virus can lay without symptoms for decades before scarring the liver, leading to cancer, organ failure and a transplant. Medicare didn’t previously cover screening, according to the Centers for Medicare and Medicaid Services, or CMS.

The decision to pay for testing “should increase the rate of diagnosis and at a minimum help CMS make informed treatment decisions,” said Ian Somaiya, an industry analyst at Nomura Securities International Inc. in New York, in an e-mail. “The net of all this points to higher Sovaldi sales.”

Gilead shares (GILD:US) rose 1.4 percent to $82.65 at 11:12 a.m. in New York trading, after increasing 55 percent in the 12 months before today. The Foster City, California-based company has said that the benefit of the medicine justifies the price.

Two spokeswomen for Gilead didn’t immediately respond to e-mails seeking comment on Medicare’s decision.

CDC Recommendation

The decision follows recommendations in 2012 and last year by the CDC and U.S. Preventive Services Task Force that all adults be screened for the virus, particularly those born between 1945 and 1965. Baby boomers account for about two-thirds of chronic hepatitis-C infections in the U.S., and military veterans are three times as likely to carry the virus, according to Medicare’s memo.

The testing “provides an opportunity for appropriate interventions to benefit the infected person by permitting for the early detection of, and potentially the prevention of, HCV-related liver disease,” the CMS memo said.

Prior to the development of Gilead’s Sovaldi, treatment of hepatitis-C entailed a regimen of two or more antiviral drugs with numerous side effects. Gilead’s Sovaldi won FDA approval in December.

To contact the reporter on this story: Alex Wayne in Washington at awayne3@bloomberg.net 

To contact the editors responsible for this story: Reg Gale at rgale5@bloomberg.net James Callan

Source - Bloomberg BusinessWeek

Monday, June 2, 2014

Outbreaks highlight infection risks associated with drug diversion

Outbreaks highlight infection risks associated with drug diversion

June 2nd, 2014 10:24 am ET - CDC's Safe Healthcare Blog

Author: Joseph Perz, DrPH, MA
Quality Standards and Safety Team Leader for the Division of Healthcare Quality Promotion, Centers for Disease Control and Prevention 

When prescription medicines are stolen or used illegally, it is called drug diversion.

Prescription opioid addiction has reached epidemic proportions and is a major driver of drug diversion . One aspect of drug diversion that is not well recognized involves healthcare personnel who steal controlled substances for their personal use. Under these circumstances, patient harm can take many forms.

These include:
Substandard care delivered by an impaired healthcare provider,
Denial of essential pain medication or therapy, or
Risks of infection (hepatitis C virus, hepatitis B virus, HIV, bacterial infection) if a provider tampers with injectable drugs.

CDC and state and local health departments have helped investigate outbreaks that occurred when healthcare providers tampered with injectable drugs. Along with my CDC colleague Dr. Melissa Schaefer and I recently published a summary of six of these outbreaks, which were investigated over the last ten years.

These outbreaks revealed gaps in prevention, detection, and response to drug diversion. To prevent diversion, healthcare facilities should enforce strong narcotics security measures and maintain active monitoring systems. Appropriate response when diversion is suspected or identified includes prompt reporting to enforcement agencies and assessment of harm to patients, including assessment of possible infection risks. 

Drug Diversion in Healthcare Settings

Medscape: Expert Video Commentary
View video here, or read transcript below. 

Read The Full Text Article; Outbreaks of Infections Associated With Drug Diversion by US Health Care Personnel

Hi. I'm Dr. Joe Perz, a healthcare epidemiologist at the Centers for Disease Control and Prevention (CDC). I'm pleased to be speaking with you today as part of the CDC Expert Video Commentary series on Medscape. I will be addressing the issue of drug diversion.

Drug diversion can be defined as any act or deviation that removes a prescription drug from its intended path from the manufacturer to the patient. Prescription opioid addiction, which has reached epidemic proportions in some areas of the United States, is a major driver of drug diversion

This commentary will focus on diversion involving healthcare personnel who steal controlled substances for their personal use. Under these circumstances, patient harm can take many forms, including substandard care delivered by an impaired provider, denial of appropriate therapy or pain control, and even infection risks stemming from tampering with injectable drugs. Healthcare professionals who divert drugs risk losing their licenses, credentials, and employment; they even risk losing their lives if they overdose. Consequences may also include litigation or imprisonment.

At CDC, I lead a group that monitors outbreaks of healthcare-associated infections. We recently published a manuscript in the journal Mayo Clinic Proceedings.[1]

In that article, we describe 6 outbreak investigations over the past 10 years in which diversion -- specifically tampering with controlled substances -- resulted in the transmission of infections. Two outbreaks involved tampering with opioids administered by patient-controlled analgesia pumps, which introduced contaminants and resulted in gram-negative bacteremia in 34 patients. The remaining outbreaks involved personnel who tampered with syringes or vials containing fentanyl. This involved, for example, self-injecting fentanyl from a syringe, replacing the contents with a clear solution such as saline, and returning the syringe to the procedure area or anesthesia cart. In these 4 outbreaks, hepatitis C virus (HCV) infection was transmitted to at least 84 patients. In each of these 4 outbreaks, the implicated professional was HCV-infected and served as the source. Nearly 30,000 patients were potentially exposed to bloodborne pathogens and targeted for notification advising testing.

Our review probably underestimates the burden of infections resulting from diversion. Making the connection between unexplained or difficult-to-detect infections on the one hand, and illicit, concealed drug diversion activities on the other hand, is extremely difficult. Our review also does not in any way adequately reflect the frequency of diversion by healthcare personnel in the United States. It has been reported that more than 100,000 US doctors, nurses, technicians, and other health professionals struggle with abuse or addiction.[2] Prescription drugs and controlled substances such as oxycodone and fentanyl are often involved. A manager of controlled substance surveillance at one hospital recently reported identifying at least 1 healthcare provider each month stealing medication from the facility.[3] What sets this institution apart from others? Perhaps nothing more than the fact that it has a program to actively monitor for diversion activity.

Patient safety and professional safety all demand effective, reliable safeguards to maintain the integrity of prescription drugs and controlled substances. Here are 3 things that you can do, whether your role is that of a manager or healthcare professional: Prevent, detect, and respond.

Prevention always comes first. Healthcare facilities are required to have systems in place to guard against theft and diversion of controlled substances. It is important that all staff understand and comply with these protocols, acting in ways to minimize unauthorized access or opportunities for tampering and misuse.

Even with such prevention safeguards, healthcare facilities must have systems to facilitate early detection. These systems can include active monitoring of pharmacy and dispensing record data, as well as having staff who are aware of and alert for behaviors and other signs of potential diversion activity.

This leads to the third action: response. For staff, this can be summarized as "see something, say something." Appropriate response at the institutional level includes assessment of harm to patients, consultation with public health officials when tampering with injectable medication is suspected, and prompt reporting to enforcement agencies.

In closing, consider the ubiquitous nature of controlled substances in many healthcare environments -- settings where you provide care or help to manage. Access to these drugs must be tightly managed and monitored for the good of your fellow staff and your patients. Maintaining the security of controlled substances is a shared responsibility. Working together, we can raise awareness and strengthen protections in this area.

Web Resources

CDC: Injection Safety
CDC: Risks of Healthcare-Associated Infections From Drug Diversion
CDC: One and Only Campaign
CDC: Impacts Related to Unsafe Injection Practices
Minnesota Hospital Association Drug Diversion Prevention Toolkit
Premier Drug Diversion

Dr. Joseph Perz is the Ambulatory and Long Term Care Team Leader for the Division of Healthcare Quality Promotion at the Centers for Disease Control and Prevention in Atlanta, Georgia. Dr. Perz entered the field of public health after training as an engineer and environmental scientist. After receiving a doctorate in public health from Columbia University, he served as an epidemic intelligence service officer with the Tennessee Department of Health. During his 15 years with the CDC, Dr. Perz has guided dozens of outbreak investigations and special studies, drawing attention to the need for injection safety and other basic infection control. He has authored or coauthored over 50 peer-reviewed journal articles, Morbidity and Mortality Weekly Report articles, and book chapters. His team's activities are currently focused on interagency collaboration, support to health departments, and partnership efforts to expand prevention activities to ambulatory and long-term care settings.

Monday HCV News Ticker - Does Cancer Treatment Bring Back HCV and Hepatitis C therapies: Dawn of a new age

 AGA Journals:

Does Cancer Treatment Bring Back HCV Infection?

Treated hepatitis C virus (HCV) infections do not return after patients receive chemotherapy or immunosuppressive therapy, researchers report in the June issue of Clinical Gastroenterology and Hepatology.

Cancer chemotherapy leads to HCV reactivation in patients with chronic infections, but little is known about the effect of chemotherapy on HCV infections that have been cured among patients with sustained viral responses (SVRs). Immunosuppressive therapies could also reverse SVRs.
Parag Mahale et al. investigated whether cancer treatments led to relapse of HCV infection among 30 patients who achieved SVRs before they were diagnosed with and treated for cancer.

Half of the patients studied had hematologic malignancies and half had solid tumors; 60% had received HCV therapy with interferon and ribavirin. Chemotherapy was started at a median of 72 months after patients achieved their SVRs, and included rituximab (27%), cyclophosphamide (23%), cisplatin (17%), or corticosteroids (37%).  The authors defined HCV infection relapse based on detection of HCV RNA in serum using commercially available assays.

Mahale et al. found that none of the patients had viral relapse after any form of cancer therapy. The authors conclude that SVRs are not affected by chemo- or immunosuppressive therapies.
Some studies have reported detection of HCV RNA in liver cells and peripheral blood mononuclear cells (PBMCs) from patients who already achieved SVRs, but little is known about the clinical significance of these observations. Mahale et al. were not able to determine whether PBMCs from patients included in their study hid some residual HCV.

Further studies are therefore needed to evaluate larger groups of patients, treated with other types of HCV therapies, to determine if these findings can be generalized to all cancer patients with a history of successfully treated HCV infection.


Hepatitis C therapies: dawn of a new age
New treatments from the likes of Merck & Co, Janssen and Gilead offer significant treatment advances

The hepatitis C virus (HCV) is a highly mutable, heterogeneous, enveloped RNA virus transmitted through the blood of infected carriers. Classified into eleven major genotypes, genotypes 1-3 have a worldwide distribution, with subtypes 1a and 1b accounting for approximately 60 per cent of infections. Due to its long latency period and constantly mutating genome, the highly infectious blood-borne pathogen has proven particularly difficult to control; worldwide, more than 170 million chronic carriers are estimated to be at risk of developing liver cirrhosis or hepatocellular carcinoma.

For more than a decade, standard of care has been based on the combination of pegylated versions of the immunomodulator interferon-alpha (IFN) and the ribonucleoside antiviral agent ribavirin (RBV), administered for 24 or 48 weeks. While these regimens can achieve viral eradication in 40-50 per cent of patients with HCV genotype 1 infection, and in approximately 80 per cent of patients with genotypes 2 and 3, they are limited by significant side effects and contraindications in a high proportion of patients.

In 2011, a new class of HCV therapeutics specifically targeting key viral growth and replication mechanisms, called direct-acting antivirals (DAAs), entered the market. HCV protease inhibitors boceprevir (Victrelis; Merck) and telaprevir (Incivo; Vertex, Janssen) were first and, while both remained dependent on the IFN + RBV backbone, the agents significantly improved virologic response rates in the genotype 1 patient population. In 2013, the approvals of the HCV NS3/4A protease inhibitor simeprevir (Olysio; Medivir, Janssen) and the HCV NS5B inhibitor sofosbuvir (Sovaldi; Gilead) signalled the beginning of a new wave of DAAs. Sofosbuvir became the first ever IFN-free HCV treatment to be approved.

Convenient all-oral treatments
Research has been driven by the need for a convenient, all-oral treatment that improves the tolerability profile of IFN-based regimens and provides efficacy across all HCV genotypes and in difficult-to-treat subpopulations, such as patients with advanced cirrhosis and those co-infected with HIV. To this end, the HCV pipeline has advanced with speed and success. Over the coming year, several IFN-free, DAA-based regimens and fixed-dose combinations (FDCs) are expected to reach the market.

Bristol-Myers Squibb's (BMS) NS5A inhibitor daclatasvir is fast approaching the finish line, with regulatory approval pending in the European Union (EU), the United States (US) and Japan for its use in combination with other antiviral agents, including sofosbuvir or the NS3 inhibitor asunaprevir (BMS). Already, the daclatasvir + sofosbuvir combination regimen is available on a compassionate-use basis in the EU. The ongoing phase 3 ALLY trials are evaluating this combination across genotypes 1-6 in both treatment-naïve and -experienced patients, as well as in cirrhotic patients and in those having undergone liver transplantation.

The asunaprevir + daclatasvir combination is currently being assessed in the phase 3 Hallmark studies. Results to date have shown that sustained virologic response at 12 weeks post-treatment (SVR12), considered to be an end-point reflective of a functional cure, was achieved in 90 per cent of treatment-naïve patients and in 82 per cent of patients unresponsive to or ineligible for IFN + RBV therapy. The dual regimen is also performing well with the addition of the NS5B inhibitor BMS 791325 (BMS). This triple DAA combination is being evaluated as an FDC in the phase 3 UNITY trials. Interim phase II results reported an SVR12 rate of 94 per cent in treatment-naïve patients with genotype 1 infection treated for 12 weeks.

The cost of novel HCV drugs remains a significant concern ... and the milestone launch of Sovaldi was dampened by controversy over its price tag 

The FDC comprising the NS5A inhibitor ledipasvir (Gilead) and sofosbuvir is also awaiting regulatory approval. Submissions were made in the EU, the US and Canada in February 2014 for its use as an IFN-free treatment for HCV genotype 1 infection, and included positive results from the phase 3 ION programme. Across the three ION studies, 1,952 patients with genotype 1 HCV infection were randomised to receive ledipasvir/sofosbuvir once daily, with or without RBV, for 8, 12 or 24 weeks. The rates of SVR12 were exceptionally high, despite more than half the study population having infection compounded by compensated cirrhosis. An intent-to-treat analysis showed that SVR12 was achieved in up to 97.7 per cent of treatment-naïve patients who received the FDC without RBV. In treatment-experienced patients, 96.4 per cent and 99 per cent achieved SVR12 when RBV was added to the 12- and 24-week regimens, respectively.

AbbVie is developing a DAA-based, IFN-free regimen centred on the protease inhibitor ABT 450. Regulatory filings were submitted in the US in April 2014, with EU submissions planned for the following month. This regimen comprises the once-daily FDC of ABT 450 (pharmacologically enhanced with ritonavir) and the NS5A inhibitor ABT 267, administered with the twice-daily non-nucleoside polymerase inhibitor ABT 333. The entire regimen is being trialled in more than seven phase 3 clinical studies, which include treatment-naïve and -experienced patients with genotype 1a or 1b HCV infection, with and without cirrhosis or co-infection with HIV. Virologic response rates to date have been impressive; in genotype 1b treatment-naïve and treatment-experienced patients, SVR12 was achieved in 99 per cent and 100 per cent of participants, respectively, when the regimen was administered without RBV. The TURQUOISE II study in cirrhotic patients has recently demonstrated SVR12 rates as high as 91.8 per cent following 12 weeks' treatment and 95.9 per cent after 24 weeks' treatment.

An IFN-free FDC comprising the NS3/4A protease inhibitor MK 5172 and the NS5A inhibitor MK 8742 is being developed by Merck. With pan-genotypic activity and improved resistance profiles compared with their first-generation counterparts, both compounds can be considered second-generation variants in their respective DAA classes. Results from the phase 2 C-WORTHY study showed promising virologic response rates in a number of patient subpopulations. According to an intent-to-treat analysis, a virologic response was observed in 98 per cent of treatment-naïve, genotype 1 patients given once-daily MK 5172/MK 8742 without RBV for 12 weeks. Of 29 patients co-infected with HCV/HIV, 100 per cent achieved a virologic response after 12 weeks' treatment. The phase 3 C-EDGE programme, scheduled to commence in June 2014, will evaluate the FDC across multiple HCV genotypes, as well as in patients with chronic kidney disease, cirrhosis, co-infection with HIV, and those on opiate substitution therapy.

Direct-acting antivirals
In addition to these late-stage regimens vying for approval, the number of DAAs in phase 2 development indicates that research remains committed to continual improvement. AbbVie is co-formulating its next-generation compounds ABT 530 and ABT 493, its ritonavir-free protease inhibitor, and Gilead has GS 5816 poised for phase 3 development with sofosbuvir. Achillion Pharmaceuticals has DAAs sovaprevir, neceprevir and ACH 3102 in the works, Idenix and Janssen are collaborating on samatasvir and TMC 647055, and phase 2 development of JNJ 56914845 (Janssen) is also underway. While the majority of DAAs in the pipeline act on the HCV NS3/4A serine protease, NS5A polymerase or NS5B polymerase, additional targets are also emerging. The HCV p7 protein is being targeted by BIT 225 (Biotron) and the HCV NS4B protein has also been identified for its potential druggability.

If HCV research has indeed been directed toward the creation of a well-tolerated, pan-genotypic, all-oral, IFN-free regimen with minimal contraindications and a high barrier to drug resistance, the late-stage results from these DAA regimens are certainly a testament to the success of these efforts. However, despite the vast improvements in efficacy and tolerability over their standard-of-care counterparts, these regimens will arrive with their own limitations.

The cost of novel HCV drugs in the marketplace remains a significant concern. The milestone launch of sofosbuvir, for example, was dampened by controversy over its $1,000 per pill price tag. With a number of regimens approaching commercialisation, an atmosphere of competition may help to mitigate this issue. In any event, access to these drugs is likely to remain a hot topic due to the proportion of the HCV population residing in developing countries. As well as its geographic dispersal, this population is characteristically diverse within itself. For this reason, it cannot be assumed that a 'boxed set' FDC product will be as efficacious for one patient as it is for another. Individual patient needs and economic factors may drive a 'mix and match' approach to tailor inter-company drug cocktails for maximal efficacy and cost-effectiveness. It is certainly hoped that in time collaborative drug-interaction studies may clinically validate such uses.

Aside from any lingering question marks or potential limitations, it cannot be denied that these are exciting times in the field of HCV therapeutics. It remains to be seen whether one or more of the aforementioned DAA-based, IFN-free regimens succeeds in providing a long-term, clinically meaningful, true 'miracle cure' for the millions of patients infected with HCV worldwide. This promising pipeline is, without doubt, one to watch.


NASH expected to top indications for liver transplantation in HCC patients
Nonalcoholic steatohepatitis is the most rapidly progressing indication for liver transplantation among patients with hepatocellular carcinoma, a recent study determined.
In a retrospective study, researchers assessed trends in the etiology of hepatocellular carcinoma (HCC) among 61,868 patients who underwent liver transplantation (LT) in the US. The cohort, drawn from the 2002 to 2012 United Network for Organ Sharing registry, included 10,061 patients with HCC.
Full Story »

Diabetes mellitus increased risk for HCC mortality among middle-aged, elderly
June 2, 2014
Middle-aged and elderly Taiwanese patients with diabetes mellitus had an increased risk for death from hepatocellular carcinoma, according to new study results.
Researchers conducted a cohort study of 50,080 Taiwanese patients (mean age, 53.9 years; 53% women) without chronic hepatitis B or C virus infection and cirrhosis between January 1998 and December 2008, to determine any associations between diabetes mellitus (DM), dyslipidemia and hepatocellular carcinoma (HCC). The follow-up period was 10 years and completed by 88% of the cohort.
Full Story »

Alimentary Pharmacology & Therapeutic

UK consensus guidelines on hepatitis C management
The latest Alimentary Pharmacology & Therapeutics reports on the 2014 UK consensus guidelines for hepatitis C management and direct-acting anti-viral therapy.


Alcoholic Hepatitis: Current Challenges and Future Directions
Alcoholic cirrhosis is the eighth most common cause of mortality in the United States and the second leading cause of mortality among all gastrointestinal diseases.[1] This may come as no surprise because the majority of the U.S. population consumes alcohol, with 1 in 10 reporting "heavy" drinking (≥3 drinks/day).[2] Fortunately, only a minority of these heavy drinkers develop significant liver disease.[2,3,4] The reasons for this are unclear, although demographic and genetic factors such as gender, ethnicity, binge drinking (5 or more drinks at a time), nutrition status including obesity, coexisting liver diseases such as hepatitis C virus (HCV) infection, and patatin-like phospholipase-3 gene polymorphism clearly play a role.[2,5–8] A recent study by Becker et al[4] indicates that younger people, women, and binge drinkers are more prone to develop alcoholic hepatitis (AH). This clinical decision meeting should take these factors into account, rather than focusing only on a precise level of alcohol consumption. AH is a clinical syndrome among subjects with chronic and active alcohol abuse characterized clinically by hepatic decompensation and portal hypertension.[9,10] Owing to the high mortality associated with this condition as well as the lack of adequate pharmacologic treatments, increasing efforts have been directed toward developing new therapies.[11] This review focuses on the challenges related to management of AH as well as future directions in the field.

FDA Okays First Device for Restless Legs Syndrome
Susan Jeffrey
The US Food and Drug Administration (FDA) today granted commercial clearance of the first device to help improve quality of sleep in patients with primary restless legs syndrome (RLS), the company announced.

The device (Relaxis, Sensory Medical Inc) is a low-profile pad; the patient lies in bed and places his or her legs on the pad, which provides vibratory counterstimulation that gradually ramps down and shuts off. The approval is based on a meta-analysis and a pooled analysis of 2 randomized, multicenter clinical trials that showed the device was superior to a placebo pad for improving sleep quality in patients with RLS, the company noted in a statement...

BMA Commends NAM’s New Hepatitis C Leaflets, Funded by Wandsworth Oasis
June 2, 2014
by Gill P

Wandsworth Oasis has been contributing towards NAM’s highly regarded information resources for people living with HIV for the last two years. Some of the funds from our first grant went towards the production of four illustrated leaflets on hepatitis C.

We were delighted to hear that the four leaflets were commended by the British Medical Association (BMA) in the recent BMA Patient Information Awards!

Hepatitis is one of the most common co-infections affecting people with HIV. It is passed on in many of the same ways as HIV and can be the cause of serious health problems. But it is treatable, and at the moment, there’s a lot of promising research in newer, better treatments for hepatitis C.

There isn’t much easy-to-read information on hepatitis C for people with HIV. In particular, there’s almost no clear and practical information about the sexual transmission of hepatitis C although it’s an increasing concern for gay men with HIV. And making a decision about whether to start hepatitis C treatment now can be difficult, with a number of pros and cons to weigh up.

The leaflets aim to explain these topics, breaking down complex health information. Each title covers a few key facts and the simple language and pictures bring the information to life.

You can find the four leaflets by following these links:
Hepatitis C
Hepatitis C treatment
How hepatitis C is passed on
How hepatitis C is passed on during sex

The project is a great example of how Wandsworth Oasis is supporting projects that are responding to important, emerging needs.

The BMA Patient Information Awards

The awards have been running since 1997, with the aim of encouraging, “excellence in the production and dissemination of accessible, well-designed and clinically balanced patient information”.

Caspar Thomson, NAM’s Executive Director, told us: ‘We are really thrilled. We could never have produced these leaflets without Wandsworth Oasis’s support and I am really pleased that they have received this praise from the BMA. Hepatitis C co-infection is a complex issue and it is vital people living with HIV have access to good quality information about it. Wandsworth Oasis has made this possible.” 

Weekend Updates -
HCV Weekend Reading; Behind evolving treatments for hepatitis C and progress toward a cure
Updated June 1 2014: Sofosbuvir Based Hepatitis C Clinical Trials - Recruiting

Healthy You
NEJM Featured Multimedia
Nut Consumption and Mortality
Y. Bao and Others
Quick Take Animation 

Sunday, June 1, 2014

HCV Weekend Reading; Behind evolving treatments for hepatitis C and progress toward a cure

Good afternoon folks, welcome to another edition of "Weekend Reading"

The sun is shinning bright in my part of the world, hope its doing the same where you live. Today, after updating the blog, Nana and the short people spent the afternoon running after flying fuzz, better known as (Santa Hair). We blew close to 32 pieces of fuzz back up to Santa.

If you get the time this weekend, after mowing the lawn, or spending time with family, take a look see at these updates.

First up is a NEJM podcast for those clinical savvy nerds; An Interview with Dr. Raymond Chung on the science behind evolving treatments for hepatitis C and progress toward a cure, if you missed the program its worth a listen.

In addition, two U.S. clinical trials sponsored by Janssen using Simeprevir in combination with Sofosbuvir for genotype 1 patients with or without Cirrhosis is now recruiting; Updated June 1 2014: Sofosbuvir Based Hepatitis C Clinical Trials.

Skim over the results from COSMOS, a study with Simeprevir and Sofosbuvir in cirrhotic and non-cirrhotic HCV genotype 1 patients presented at AASLD 2013, here, final phase II data presented at EASL 2014, here.  Read more about Sofosbuvir based regimes here, Gilead's Sofosbuvir and Ledipasvir fixed dose combination here,  Sovaldi (Sofosbuvir), here and bookmark this for later; Sofosbuvir in the Treatment of Hepatitis C-A Review of Its Clinical Potential.

In May Janssen Submitted a supplemental NDA to the U.S. FDA for OLYSIO™ (Simeprevir) in Combination with Sofosbuvir. 

Just updated on the website is a collection of research, news and health tips on viral hepatitis and liver health.

As we all know, the weekend wouldn't be complete without reading HCV Advocate's June Newsletter.

In This Issue:
HCV Drugs
Alan Franciscus, Editor-in-Chief

Lucinda K. Porter, RN

HEALTHWISE: Hepatitis C & Liver Cancer (HCC)
Lucinda K. Porter, RN

HCV Advocate Eblast
Stay informed on the latest news...click
here to register for email alerts

Finally, on the blog is an index of current articles discussing the continuing controversy over the high price of Solvadi:
The coming epidemic..
A medical breakthrough actually worth paying for....
Why does Gilead's Sovaldi cost $84K in the U.S. and $57K in Britain?
At $1,000 per pill, new Hepatitis C drug has insurers and CCOs scratching their heads...
The Price is Right: New Hepatitis C Drug is Really a Priceless Breakthrough....
Check out the headlines here.....

Enjoy this lovely weekend, until next time.

Always Tina

Updated June 1 2014: Sofosbuvir Based Hepatitis C Clinical Trials - Recruiting

Sofosbuvir Based Hepatitis C Clinical Trials - Recruiting
The hepatitis C clinical trials on this page are not a complete list; to learn more about HCV trials or to find out if a study is enrolling patients in your area, please click  here. View additional hepatitis trials updated in the last 30 days @ ClinicalTrials.gov 

*Updated June 1 2014
*Recruiting - United States
Efficacy and Safety Study of Simeprevir in Combination With Sofosbuvir in Participants With Chronic Hepatitis C Virus Infection Without Cirrhosis
Wednesday, April 02, 2014 12:00 PM
Condition:   Hepatitis C Virus Infection
Interventions:   Drug: Simeprevir;   Drug: Sofosbuvir
Sponsor:   Janssen Infectious Diseases BVBA
Recruiting - verified May 2014
ClinicalTrials.gov Identifier:

*Recruiting - United States
Efficacy and Safety Study of Simeprevir in Combination With Sofosbuvir in Participants With Genotype 1 Chronic Hepatitis C Virus Infection and Cirrhosis
Wednesday, April 02, 2014 12:00 PM
Condition:   Hepatitis C Virus Infection
Interventions:   Drug: Simeprevir;   Drug: Sofosbuvir
Sponsor:   Janssen Infectious Diseases BVBA
Recruiting - verified May 2014
ClinicalTrials.gov Identifier:

Recruiting - India
Safety and Efficacy of Sofosbuvir Plus Ribavirin in Treatment-Naive Adults With Chronic Genotype 1 or 3 HCV Infection
Wednesday, February 26, 2014 12:00 PM
Condition:   Chronic HCV Infection
Interventions:   Drug: Sofosbuvir;   Drug: RBV
Sponsor:   Gilead Sciences
Recruiting - verified May 2014
ClinicalTrials.gov Identifier:

Recruiting - United States
Efficacy and Safety of Ledipasvir/Sofosbuvir Fixed-Dose Combination and Sofosbuvir + Ribavirin for Subjects With Chronic Hepatitis C Virus (HCV) and Inherited Bleeding Disorders
First received: April 18, 2014
Condition:   Chronic HCV Infection
Interventions: Drug: LDV/SOF
Drug: Sofosbuvir
Drug: Ribavirin
Sponsor:   Gilead Sciences
Recruiting - verified April 2014
ClinicalTrials.gov Identifier:

Recruiting - New Zealand
Sofosbuvir Containing Regimens for the Treatment of Chronic HCV Infection in Subjects With Chronic Genotype 1, 2, 3, or 6 HCV Infection 
Condition: Chronic Hepatitis C
Interventions: Drug: LDV/SOF FDC; Drug: SOF; Drug: RBV; Drug: PEG; Drug: GS-9669; Drug: GS-5816
Sponsor: Gilead Sciences
Recruiting - Last Verified: April 2014
ClinicalTrials.gov Identifier:

Recruiting - France
Efficacy and Safety of Ledipasvir/Sofosbuvir Fixed-Dose Combination in Treatment-Naïve and Treatment-Experienced Subjects With Chronic Genotype 4 or 5 HCV 
Infection Conditions: Chronic Genotype 4 HCV; Chronic Genotype 5 HCV
Intervention: Drug: LDV/SOF
Sponsor: Gilead Sciences 
Recruiting - Last Verified: April 2014
ClinicalTrials.gov Identifier:

Recruiting - Belgium, Austria, Australia, New South Wales, Canada, Quebec, Canada, Ontario, Canada, British Columbia, Canada, Alberta, United Kingdom, Switzerland, Spain, New Zealand, Netherlands, Italy, Germany, and France
Ledipasvir/Sofosbuvir Fixed-Dose Combination Plus Ribavirin in Subjects With Chronic HCV With Advanced Liver Disease or Post-Liver Transplant
Condition: Chronic HCV Infection
Interventions: Drug: LDV/SOF; Drug: RBV
Sponsor: Gilead Sciences 
Recruiting - Last Verified: April 2014
ClinicalTrials.gov Identifier:

Recruiting - United States
Phase III Daclatasvir, Sofosbuvir, and Ribavirin in Cirrhotic Subjects and Subjects Post-liver Transplant
Thursday, January 09, 2014 12:00 PM
Condition:   Hepatitis C
Interventions:   Drug: Daclatasvir;   Drug: Sofosbuvir;   Drug: Ribavirin
Sponsor:   Bristol-Myers Squibb
Recruiting - verified March 2014
ClinicalTrials.gov Identifier:

Recruiting - United States, Austria, Germany, Netherlands, New Zealand, Puerto Rico
Sofosbuvir Plus Ribavirin in Subjects With HCV Infection and Renal Insufficiency
Condition: HCV Infection
Interventions: Drug: Sofosbuvir; Drug: RBV
Sponsor: Gilead Sciences
Recruiting - Last Verified: April 2014
ClinicalTrials.gov Identifier:

Recruiting - United States, Canada, Puerto Rico, and New Zealand
Efficacy and Safety of Ledipasvir/Sofosbuvir Fixed-Dose Combination for 12 Weeks in Subjects With Chronic Genotype 1 or 4 HCV and HIV-1 Co-infection
Tuesday, February 25, 2014 12:00 PM
Conditions:   Hepatitis C Virus;   HIV
Interventions:   Drug: LDV/SOF;   Drug: RBV
Sponsor:   Gilead Sciences
Recruiting - verified May 2014
ClinicalTrials.gov Identifier:
Monday, ‎May ‎05, ‎2014, ‏‎12:00:00 PM
Condition: Hepatitis C
Interventions: Drug: MK-5172/MK-8742 FDC; Drug: Sofosbuvir
Sponsor: Merck Sharp & Dohme Corp.
Not yet recruiting - verified May 2014

Efficacy and Safety of Sofosbuvir+Ribavirin in Genotype 2 HCV-infected U.S. Veterans With Cirrhosis
Tuesday, April 29, 2014 12:00 PM
Condition:   Hepatitis C Virus Infection
Interventions:   Drug: Sofosbuvir;   Drug: RBV
Sponsor:   Gilead Sciences
Not yet recruiting - verified April 2014

Pilot Study to Assess Efficacy and Safety of Sofosbuvir/Ledipasvir Fixed-dose Combination in Treatment Experienced Subjects With Hepatitis C Virus (HCV) Genotype 1 - HIV Co-infection
Thursday, April 24, 2014 12:00 PM
Conditions:   Viral Hepatitis C;   HIV
Intervention:   Drug: Sofosbuvir/Ledipasvir fixed dose
Sponsor:   French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS)
Not yet recruiting - verified April 2014

Sofosbuvir Plus Ribavirin For Acute Hepatitis C in HIV-infected Individuals (SWIFT-C)
Tuesday, April 29, 2014 12:00 PM
Conditions:   HIV-1 Infection;   Hepatitis
Interventions:   Drug: Ribavirin;   Drug: Sofosbuvir
Sponsors:   AIDS Clinical Trials Group;   National Institute of Allergy and Infectious Diseases (NIAID)
Not yet recruiting - verified April 2014

Take the time to learn more about HCV agents currently in clinical trials by reviewing new research presented at the International Liver Congress 2014, or click here to view; "Hepatitis C Treatment Goes Viral: Let's Talk About Oral Therapies" a new webcast featuring commentary on five different hepatitis C treatment scenarios. Join host Ira M. Jacobson, MD along with a panel of experts discuss current therapies for chronic hepatitis C, and the latest trial results in this enjoyable easy to follow webcast.

For additional information visit HCV Advocate News and Pipeline for trial updates;

Sovaldi - When ‘miracle’ cures, cost collide

Demand for expensive hepatitis C drug strains insurers

When ‘miracle’ cures, cost collide

By Robert Weisman | Globe Staff June 01, 2014

“My virus is now undetectable,” said Barnstable resident Laurel Welch, 65, a retired nurse who contracted hepatitis C through contact with contaminated blood 25 years ago and began taking Sovaldi in January. “I was so sick for so long. Now I’ve got a new life.”
Sovaldi, sold by California-based Gilead Sciences Inc., may also represent the future of cutting-edge drugs in another way: At $1,000 a pill and $84,000 for a full treatment regimen — plus the cost of companion medicines — it’s straining the finances of insurance companies.
Demand for Sovaldi is growing so fast that insurers have begun restricting who can immediately get it, to the dismay of patients.
Continue Reading.....

Related: Reducing the cost of new hepatitis C drugs 
An index of articles pointing the reader to current information and controversy over the high price of Solvadi:
The coming epidemic..
A medical breakthrough actually worth paying for....
Why does Gilead's Sovaldi cost $84K in the U.S. and $57K in Britain?
At $1,000 per pill, new Hepatitis C drug has insurers and CCOs scratching their heads...
The Price is Right: New Hepatitis C Drug is Really a Priceless Breakthrough....
Continue reading.....