Saturday, January 31, 2015

Weekend Reading - Patient Friendly Audio discussing interferon-free regimens for the treatment of HCV

Patient Friendly Audio discussing interferon-free regimens for the treatment of HCV 

Hello everyone, getting ready for the big game? My son sure is, as for me, not so much. Today I'm more excited to introduce a new patient friendly web seminar discussing interferon-free regimens for the treatment of HCV. Go CCO!

So grab a few wings, sit back and listen to Dr. Mark Sulkowski summarize treatment considerations for hepatitis C patients using new interferon-free regimens based on AASLD/IDSA joint guidelines, launched yesterday over at Clinical Care Options (CCO)

Not To Be Missed
The good doctor follows up the program with an in-depth question and answer session. 

Key Points
Peginterferon is no longer a first line therapy for any patient.
We now have three FDA approved interferon free regimens for genotype 1.
No differences in how we treat co-infected patients with HIV compared to mono-infected except for the point of drug interactions.

Treatment in genotype 1a and 1b.
Treatment duration
Treatment with or without ribavirin for both treatment experienced or treatment naive patients.
Treatment for patients with or without cirrhosis.
Treatment in liver transplantation patients. 

Summary Of Questions
Biggest HCV cure is patient adherence
Duration of therapy for patients with cirrhosis
Monitoring patients who achieve SVR for liver cancer.
Staging fibrosis
Current recommendations in treating Genotype 3.
Initiating treatment, wait or treat.
Resistance testing
and more.....

Free registration is available, here.

Incorporating the Latest AASLD/IDSA Guidance on HCV Management
Source: HCV Alerts: Rapid Response to Practice-Changing Advances

Expert Highlight
Dr. Mark Sulkowski discusses how to incorporate the latest AASLD/IDSA guidance on HCV management into clinical practice. (30 Minutes)
Format: mp3
File size: 21.69 MB
Date posted: 1/30/2015
Begin Here....

In this downloadable slideset, Dr. Mark Sulkowski highlights how to incorporate the latest AASLD/IDSA guidance on HCV into clinical practice.

Format: Microsoft PowerPoint (.ppt)
File size: 565 KB
Date posted: 1/20/2015

Enjoy the game tomorrow!

Friday, January 30, 2015

PODCAST: Baby Boomers Should Get Tested For Hep-C

Posted Friday, January 30th 2015 @ 9am

Houston's Morning News with Matt Patrick welcomes KTRH Medical expert Dr. Joe Galati, to discuss more about baby boomers who overall, need to be tested for Hep C. Some reports advise against it, but Dr. Galati defuses that by explaining why more baby-boomers have the Hepatitis C today, adding it's highly curable. Listen in for details.


Hot on the trail of the hepatitis-liver cancer connection

Hot on the trail of the hepatitis-liver cancer connection

Using whole genomic sequencing, scientists from RIKEN in Japan have for the first time demonstrated the profound effect that chronic hepatitis infection and inflammation can have on the genetic mutations found in tumors of the liver, potentially paving the way to a better understanding of the mechanisms through which these chronic infections can lead to cancer. Primary liver cancer is the third leading cause of cancer death worldwide, and recent studies have shown that particularly in Asia, infection with either hepatitis B or C is often associated with such cancers.

For the study, which was published in Nature Communications, the group performed whole genomic sequencing on 30 individual tumors classified as liver cancer displaying a biliary phenotype. This type of cancer originates in the liver, but is different from hepatocellular carcinoma, the dominant form of primary liver cancer, and is generally more aggressive, with poorer prognosis. They compared the data with 60 of the more-common hepatocellular carcinoma tumors. To study gene expression, they then examined RNA sequencing data from 25 of the biliary-phenotype cancers and 44 hepatocellular cancers.

Thursday, January 29, 2015

Hepatitis C Scorecard: Express Scripts Drafts Inferior Drug —Express Scripts' peers choose Harvoni/Solvadi over Viekira Pak.

Drafts Inferior Drug  —Express Scripts' peers choose Harvoni/Solvadi over Viekira Pak.
by Jim Davis
Adverse Events

As we've stated over the past several weeks, AdverseEvents is not a fan of drug manufacturer and payer exclusivity deals. We believe strongly that they are not in the best interest of drug safety and set a dangerous precedent.

The veracity of our beliefs was demonstrated by the results revealed from the comparative safety research we conducted on Abbvie's ombitasvir/paritaprevir/ritonavir; dasabuvir (Viekira Pak) and Gilead's ledipasvir and sofosbuvir (Harvoni/Sovaldi). Viekira Pak's inferior safety profile confirmed that Express Scripts made the wrong decision to exclusively place it on its' National Preferred Formulary.

Since our initial comments on Express Scripts' and CVS' respective deals, most of the other big name payers have made similar arrangements. Here's the breakdown of who is covering what (publicly) as of Jan. 27, 2015:

Gilead's Harvoni / SovaldiAbbvie's Viekira PakBoth Drugs
CVS HealthcareExpress ScriptsPrime Therapeutics

If we take Prime out of the mix, that is 5-1 in favor of Harvoni/Sovaldi.
I guess we aren't the only ones that think Express Scripts made the wrong decision. Public drug safety and long term cost savings should always win out over short-term profits.
You can see our head-to-head comparison of the safety profiles of Harvoni, Sovaldi and Viekira Pak drugs here.

Related Read:
Did Express Scripts Choose the Right Hepatitis C Drug?
Jim Davis is executive vice president of Adverse Events. Adverse Events is a healthcare informatics company that improves patient safety and reduces systemic healthcare costs through the comprehensive analysis of postmarketing drug side effect data. AEI makes postmarketing drug safety data accessible, actionable, and predictable, providing services to enterprise markets including managed care organizations, the pharmaceutical industry, and financial institutions.


Intercept Receives Breakthrough Therapy Designation From FDA for Obeticholic Acid for Nonalcoholic Steatohepatitis (NASH) With Liver Fibrosis

Intercept Receives Breakthrough Therapy Designation From FDA for Obeticholic Acid for Nonalcoholic Steatohepatitis (NASH) With Liver Fibrosis 

Breakthrough Therapy Designation for Treatment of NASH With Liver Fibrosis Reinforces Potential for OCA to Address Unmet Medical Need in Patients With This Serious Condition

NEW YORK, Jan. 29, 2015 (GLOBE NEWSWIRE) -- Intercept Pharmaceuticals, Inc. (Nasdaq:ICPT) (Intercept), today announced that its investigational product obeticholic acid (OCA) has received "breakthrough therapy designation" from the U.S. Food and Drug Administration (FDA) for the treatment of patients with nonalcoholic steatohepatitis (NASH) with liver fibrosis. This indication constitutes a population of patients with a serious and life-threatening condition reflected by a higher risk of progression to cirrhosis and liver failure. OCA is currently being developed for the treatment of several chronic liver diseases, including primary biliary cirrhosis (PBC), NASH and primary sclerosing cholangitis (PSC).

"We are very pleased to have received breakthrough therapy designation for NASH with liver fibrosis, as it will enable us to work closely with FDA to finalize the design of our Phase 3 program," said Mark Pruzanski, M.D., President and Chief Executive Officer of Intercept. "This designation underscores a recognition of the urgent need to bring novel treatments to NASH patients who have developed liver fibrosis, which is expected to make this serious disease the leading cause for liver transplant in just the next few years. As a first-in-class FXR agonist, we believe OCA has the potential to be an important treatment option for patients with no currently approved medicines."

Breakthrough therapy designation for OCA was based on clinical efficacy and safety data from two placebo-controlled, Phase 2 clinical trials of OCA. A Phase 2 trial in 64 patients with nonalcoholic fatty liver disease (NAFLD) assessed the impact of OCA treatment on insulin sensitivity (published in Gastroenterology in June 2013). The FLINT Phase 2 trial in 283 patients with NASH assessed the impact of OCA treatment on liver histology and fibrosis (published in The Lancet in November 2014).

The breakthrough therapy designation was created by the FDA to speed the availability of new therapies for serious or life-threatening conditions. Drugs qualifying for this designation must show credible evidence of a substantial improvement on a clinically significant endpoint over available therapies, or over placebo if there is no available therapy. The designation confers several benefits, including intensive FDA guidance and discussion and eligibility for submission of a rolling NDA.

About Nonalcoholic Steatohepatitis

NASH is a serious chronic liver disease caused by excessive fat accumulation in the liver that induces chronic inflammation which leads to progressive fibrosis (scarring) that can lead to cirrhosis, eventual liver failure and death. There are currently no drugs approved for the treatment of NASH. Studies have shown that 21-26% of NASH patients will develop cirrhosis over 8.2 years of follow-up and that liver-related mortality due to this disease is ten-fold that of the general population. According to recent epidemiological studies, it is estimated that more than 10% of the U.S. adult population has NASH with more than 60% of patients (potentially more than 14 million in total) believed to have liver fibrosis or cirrhosis due to progression of the disease. The proportion of liver transplants attributable to NASH has increased rapidly in past years and by 2020 the disease is projected to become the leading indication for liver transplant ahead of chronic hepatitis C and alcoholic liver disease. NASH patients with fibrosis are at greater risk of progressing to cirrhosis, liver failure and cancer.

Wednesday, January 28, 2015

UnitedHealth backs Gilead's Harvoni as preferred hepatitis C treatment

UnitedHealth backs Gilead's Harvoni as preferred hepatitis C treatment

Wed Jan 28, 2015 5:36pm EST
(Reuters) - UnitedHealth Group Inc, the largest U.S. health insurer, on Wednesday backed Gilead Sciences Inc's Harvoni as the preferred hepatitis C treatment on its 2015 commercial drug coverage list, another victory for Gilead over competitor AbbVie Inc.

Gilead and AbbVie have been battling for hepatitis C market share since the approval in December for an AbbVie drug that challenges Gilead's blockbusters. Insurers and pharmacy benefit managers have been striking deals for preferred or exclusive status in exchange for discounts for 2015.

UnitedHealth's drug coverage list, which is effective Feb. 1, applies to all of the company's commercial, fully insured customers who use its Optum RX pharmacy benefit manager and self-insured customers such as large employers who follow the drug list.

The update to the formulary, available on the company's website, also applies to its Medicaid, Medicare and military contracts.

"We are constantly working to deliver value and manage costs for customers and consumers throughout our business," UnitedHealth spokesman Tyler Mason said in a statement.

Gilead declined to comment.

Gilead set off a firestorm last year when it launched a breakthrough treatment for hepatitis C called Sovaldi that carries an $84,000-per-treatment price tag.

Insurers, including UnitedHealth, were taken by surprise by its cost and called it out as an unexpected hit to profits last year.

Express Scripts, a pharmacy benefit manager, pushed back against the price of Sovaldi and Gilead's follow-up drug Harvoni, which has a list price of $93,400. It backed AbbVie's Viekira Pak, saying it had gotten a significant discount.

Analysts and investors say the treatments are being discounted by at least 30 percent. The companies have declined to comment.

UnitedHealth is the last of the top three U.S. insurers to strike a deal with either Gilead or AbbVie. Reuters reported two weeks ago that Aetna Inc had backed Gilead, as have Anthem Inc and Humana Inc. Pharmacy benefit manager CVS Health also went with Gilead while smaller competitor Prime Therapeutics kept both on its list.

The state of Missouri earlier this week said it had selected AbbVie's Viekira Pak for Medicaid patients who meet certain criteria, and said the agreement would reduce treatment costs by 30 to 40 percent.

UnitedHealth has 45 million medical customers. Of those, 18 million are employed by companies that are self-insured and use UnitedHealth to administer their plan benefits; not all those employers follow UnitedHealth's commercial drug guideline or use UnitedHealth for their drug benefits.

Gilead shares, which closed down 2.5 percent at $102.45, were trading slightly higher in after-hours activity at $103.11.

(Reporting by Caroline Humer; Additional reporting by Bill Berkrot; Editing by Alan Crosby and Leslie Adler)

Tuesday, January 27, 2015

PBM EnvisionRx chooses Gilead hepatitis C drugs for its formulary

PBM EnvisionRx chooses Gilead hepatitis C drugs for its formulary
Mon Jan 26, 2015 2:42pm EST

(Reuters) - Pharmacy benefits manager EnvisionRx said on Monday it reached an agreement to provide its customers with Gilead Sciences Inc's hepatitis C drugs on an exclusive basis, the latest Gilead victory in a market share battle with AbbVie over their new treatments for the liver destroying virus.

EnvisionRx said Gilead's Sovaldi and its newer two-drug combination pill Harvoni would be available on its formulary, with other hepatitis C drugs, such as AbbVie's Viekira Pak, allowed only as an exception in some cases.

It was not disclosed how much of a price discount EnvisionRx negotiated from Gilead to secure the agreement.

"The safety and efficacy profile of Gilead's HCV products, coupled with the most competitive pricing in the drug class, have solidified EnvisionRx's choice to place Gilead's products in an exclusive and preferred formulary position," said EnvisionRx President Dawn Sherman in a statement.

Express Scripts Holding, the largest U.S. pharmacy benefits manager (PBM) which had complained about the high cost of Gilead's first to market treatment, fired the first shot in the hepatitis C price war days after the AbbVie rival treatment was approved. It gave Viekira Pak preference on its formulary, excluding Gilead's drugs.

Gilead then locked up formulary exclusivity for Harvoni with CVS Health, the second largest U.S. PBM.

PBMs negotiate drug pricing for employers and health plans. Health insurers have also chosen sides after negotiating their own discount deals following the Express Scripts move.

Aetna, Anthem and Humana chose Gilead drugs as their preferred treatment, while PBM Prime Therapeutics kept both on its list.

Both treatments have demonstrated an ability to cure well over 90 percent of patients, although Gilead's Harvoni involves fewer drugs than Viekira.

Harvoni, which combines Sovaldi with another drug, has a list price of $94,500 for 12 weeks of treatment. Viekira Pak was listed at about $83,300.

Analysts believe the companies have been providing discounts of up to 30 percent, although the specific negotiated rebates have not been disclosed.

EnvisionRx provides services for Medicare Part D plans as well as government paid or subsidized insurance through Medicaid, CHIP and individual exchange plans.

(Reporting by Bill Berkrot and Caroline Humer; editing by Gunna Dickson)
Source - Reuters

Quest in broad deal with CDC for hepatitis analysis

Quest in broad deal with CDC for hepatitis analysis
Tuesday, January 27, 2015 2 p.m. CST

(Reuters) - Laboratory testing company Quest Diagnostics Inc said on Tuesday it had signed a $520,000 agreement with the Centers for Disease Control and Prevention to identify trends in screening, diagnosis and treatment of four strains of viral hepatitis.

Quest will provide the U.S. public health agency with analytics and access to Quest's national database of clinical testing hepatitis data, which includes information from more than 20 billion test results.

The agreement expands on Quest's previous efforts with the CDC on hepatitis C testing data for Baby Boomers, or individuals born between 1945 and 1965, one of the groups most exposed to the virus.

The government in 2012 recommended that Baby Boomers be screened for hepatitis C, which can cause death.

The expanded agreement aims to identify trends in screening for hepatitis A, B, C and E and will focus on data for hepatitis B and C in pregnant women to find possible gaps that the CDC could use to target screening and treatment.

The data have been modified to protect the identity of the patients.

"If you can get people diagnosed, then the next obvious stage is to get them into care," said Rick Pesano, medical director for infectious diseases at Quest.

Treatment for hepatitis C has changed dramatically since Gilead Sciences Inc introduced its Sovaldi drug in December of 2013 with few side effects. It has since introduced a second combination drug Harvoni and AbbVie Inc has launched a competitor that offers similar cure rates above 90 percent.

(Reporting by Caroline Humer; Editing by Richard Chang)
Source - Reuters

Monday, January 26, 2015

Current and Future HCV Therapy-Do We Still Need Other Anti-HCV Drugs?

Liver International
Current and Future HCV Therapy-Do We Still Need Other Anti-HCV Drugs?

Salvatore Petta, Antonio Craxì
Liver International. 2015;35(s1):4-10.

Abstract and Introduction
Eradication of hepatitis C virus (HCV) infection, at least in compensated patients, can help improve the outcomes of liver disease such as cirrhosis, hepatocellular carcinoma (HCC) and liver transplantation, as well as perhaps extra-hepatic complications such as diabetes and cardiovascular risk. In the past few years, the landscape of antiviral therapy has evolved at a breathtaking pace from pegylated interferon (PEG-IFN) plus ribavirin (RBV) (PEG-IFN/RBV) to IFN-based strategies combining direct acting antivirals (DDAs) with PEG-IFN/RBV and finally IFN-free combinations of DAAs. In particular with these most recent developments, treatment regimens have become shorter, safer and even more effective, with a wide range of indications. Nevertheless, research continues and newer antiviral drugs are still under development. At a point when a >90% sustained virological response (SVR) is being claimed with all new available regimens, pharmacological and clinical research should be addressing unresolved areas, such as cases of suboptimal SVR or to increase effectiveness rather than pursuing the development of new 'me-too' drugs. The issues which should be given priority for further development include the following:
  • Improving the results of IFN-free regimens in patients with genotype 3 (HCV-3) infection.
  • Identifying the indications for the treatment in patients with compensated and decompensated cirrhosis.
  • Identifying standardized or personalized backup strategies in patients who do not respond to IFN-free regimens. Finally, because of financial constraints, the high cost of IFN-free strategies prevents their universal use in CHC patients and coverage by national healthcare systems. Thus, efforts must be made to document cost-effectiveness in all clinical scenarios and to develop more affordable IFN-free regimens.
The estimated global prevalence of hepatitis C virus (HCV) infection is 2.2%, corresponding to roughly 130 million HCV-infected individuals worldwide.[1] HCV is one of the main causes of chronic liver disease leading to cirrhosis, hepatocellular carcinoma (HCC) and liver transplantation worldwide. In addition, recent data also suggests that HCV infection increases the risk of morbidity and mortality because of cardiovascular diseases.[2]

A sustained virological response (SVR) is a well validated clinically relevant surrogate outcome in the management of chronically infected HCV patients because viral eradication not only prevents the occurrence of cirrhosis in chronic hepatitis C (CHC),[3] but also the development of its complications in patients with compensated cirrhosis.[4–7] In addition, as observed for HBV-related cirrhosis, SVR might improve the prognosis in patients with decompensated cirrhosis who are or are not awaiting liver transplantation, by compensating liver disease, or by influencing the recurrence of HCV-related cirrhosis and liver failure in the post-transplant setting.

In the past few years, the landscape of antiviral care in patients with chronic HCV has changed quickly; thanks to the increased understanding of the biology of HCV replication and the identification of proteins blocking the key steps. In patients with genotype1 (HCV-1) dual therapy (DT) with peginterferon alfa (PEG-IFN) and ribavirin (RBV) was replaced by PEG-IFN-based triple therapies (TT) with first generation protease inhibitors (PI)-boceprevir (BOC) or telaprevir (TVR). Recently these latter regimens were replaced by simeprevir (SIM) or sofosbuvir (SOF)-based schedules.[8–10] The two latter regimens, combined with PEG-IFN/RBV, resulted in SVR rates ranging from 30% to 92%, also reducing the treatment duration and side-effects. In HCV genotypes 2 and 3 patients, PEG-IFN/RBV strategies were replaced by SOF plus RBV for HCV-2 patients with SVR rates above 90%,[8,11–13] and by SOF plus RBV or SOF plus PEG-IFN/RBV in HCV-3 patients where the addition of PEG-IFN increases SVR rates.[8,11–13] Finally, data on small cohorts of HCV-4 patients showed that compared to DT, TT regimens based on SOF or SIM achieved SVR rates similar to that reported in HCV-1 patients.[8]

At present, drugs registered in Europe include SIM, SOF and Daclatasvir (DAC), which are combined with PEG-IFN/RBV in HCV-1 and HCV-4 patients with the SVR rates mentioned above, by an off-label combination (SOF/SIM or SOF/DAC or DAC/SIM) with/without RBV in pilot studies of small groups of patients, or in combination with RBV in HCV-2 and HCV-3 patients (for SOF only).

Recent clinical trials have shown that all oral IFN-free regimens combining the different DAA–SOF/Ledipasvir(LED) and Paritaprevir(PAR)/Dasabuvir(DAS)/Ombitasvir(OMB) achieve SVR rates ranging from 90% to 100%, independent of the severity of liver damage, the pattern of previous response to DT or first-generation PI, and without significant side-effects.[12–18] These combinations, which should be registered and available in Europe in early 2015, are characterized by a short duration (8–12 weeks), oral administration with a few pills, and by a pangenotypic profile of effectiveness for SOF/LED, but restricted efficacy in HCV-1 (and perhaps HCV-4) for the AbbVie combination.

The next steps in the clinical development of anti-HCV therapy are expected in late 2015–early 2016 with the availability of pangenotypic ultrarapid (4–8 weeks) single pill regimens such as Grazoprevir/MK8742, SOF/GS5816, and BMS791325/DAC/Asunaprevir.

These advances have obviously resulted in innovations in IFN-based regimens.[19] They have resulted in SVR rates >90% with well tolerated IFN-free regimens that represent a new challenge for the treatment of HCV-related liver disease, and create new frontiers for tolerability, safety and the consequences of treatment in untreated groups such as those with decompensated cirrhosis waiting or not for liver transplantation. Thus, the key question is whether future developments should focus on new antiviral regimens, or clinical development in as yet unresolved areas? We feel that available and soon to be available drugs are generally extremely effective even if certain issues (Fig. 1) require further study: (i) suboptimal performance in patients with HCV-3; (ii) treatment of patients with compensated and decompensated cirrhosis; (iii) backup strategies in patients who do not respond to IFN-free regimens; (iv) the costs of drugs.

Figure 1.
Hot topics for the treatment of patients with chronic hepatitis C using IFN-free regimens.

The next section of this review will focus on these issues, reporting available data and suggesting future directions for clinical development.

Patients With Genotype 3 Infection are the Most Difficult to Treat With DAAs
When PEG-IFN/RBV was the treatment for HCV, the same regimen was administered to all subjects and patients were defined as easy or difficult to treat according to viral genotype. HCV- 1 and 4 were considered to be difficult-to-treat and 2 and 3 were considered to be easy to treat.[20] The SVR rates in the latter group were above 80% with shorter treatment.

The availability of IFN-free regimens has confirmed that HCV-2 patients are easy to treat while the paradigm for HCV-3 patients has been reversed compared to 'older, difficult-to-treat' HCV-1 patients. In fact, today with available DAAs, patients with HCV-3 are the most difficult to treat patients (Fig. 2). Results with an IFN-free regimen in HCV-3 patients were initially very encouraging in a small phase II study showing that 12-weeks of SOF/RBV resulted in an SVR in all HCV-2 and 3 patients.[21] In other promising preliminary results, large phase III studies in HCV-2 and 3 treatment-naïve (Fission),[8] experienced (Fusion),[11] and IFN intolerant or unwilling patients (Positron),[8] were begun to assess the effectiveness of 12–16 weeks of SOF/RBV. Overall, these studies have shown that surprisingly, while 12 weeks of SOF/RBV resulted in an SVR in HCV-2 patients independent of previous exposure to PEG-IFN/RBV and the severity of fibrosis, the latter two factors were significant for HCV-3 patients. Specifically, 12 weeks of therapy in treatment-naïve patients resulted in an SVR in 61% and 34% of non-cirrhotic and cirrhotic patients respectively.[8] Moreover the SVR rates in non-cirrhotic patients were 37% and 63% in experienced patients, in the 12- and 16- week course, respectively, and 19% and 61% in the 12- and 16-week course in non-cirrhotic patients respectively.[8,11] In particular, treatment failures were all related to relapse but not virological breakthrough confirming the high genetic barrier to resistance of SOF. These results suggest that strategies to improve SVR rates with an SOF containing regimen in HCV-3 patients should take into account an extension of prior therapy, or the addition of another anti-HCV drug (DAA or immunomodulator). Extending treatment to 24 weeks of SOF/RBV was evaluated in the Valence trial resulting in an overall SVR rate of 83%.[12,13] In particular, this was the result of higher SVR rates in treatment-naïve (93% and 92% in patients without and with cirrhosis respectively), and experienced patients without cirrhosis (87%) while rates were lower in experienced (61%) patients with cirrhosis. These results identified the difficult- to-treat category of patients and suggested that the SVR could be improved by adding another anti-HCV drug. This hypothesis was tested in two small studies. The Lonestar-2 study tested TT with PegIFN/SOF/RBV for 12 weeks in treatment-experienced HCV-2 and 3 patients.[22] The SVR in HCV-3 patients was 83% with no difference in relation to baseline cirrhosis (SVR 83% vs 83% respectively). The second study tested a combination of DAC/SOF resulting in an SVR of 89% of 18 treatment-naïve patients with HCV-3.[23]

Figure 2.

Treatment strategies in treatment naïve (A) and experienced (B) patients with HCV-3 infection with direct antiviral agents. Results from Fission (8) Fusion (11), Valence (12), Lonestar-2 (22) RCTs and Sulkowski et al. (23).

These data suggest that SOF/PEG-IFN/RBV is the most effective treatment in HCV-3 treatment-experienced patients with cirrhosis, and that this regimen is also as effective in all other HCV-3 patients as a 24 week course of SOF/RBV. Despite these strategies certain unresolved issues remain: (i) the inability to treat patients with advanced cirrhosis using an IFN- based regimen, and (ii) the high cost of a 24- week course of SOF. Thus, further research in DAAs is necessary in patients with HCV-3 to validate available data in larger cohorts and test promising new DAA combinations such as Grazoprevir/MK8742, SOF/GS5816, BMS791325/DAC/Asunaprevir, and others.

Patients With Compensated or Decompensated Cirrhosis are Candidates for IFN-free Regimens
The option of using DAAs and combining them in safe and effective IFN-free regimens extends the landscape of antiviral treatment. This is especially true in patients who are at risk of complications or in whom IFN-containing strategies are contraindicated and for whom an SVR could significantly improve the liver-related prognosis. These patients have advanced fibrosis/compensated cirrhosis or decompensated cirrhosis. Results in the former group can be found in analyses of clinical studies with a low number of patients with advanced fibrosis/cirrhosis, and one study that was specifically designed to evaluate the effectiveness of IFN-free regimens in patients with compensated cirrhosis. The ION-1 and ION 2 trials are phase III clinical studies assessing the effectiveness of SOF/LED for 12- or 24-weeks with and without RBV in HCV-1 treatment-naïve (ION-1)[12,13] or experienced (ION-2)[14] patients. The studies included 865 and 440 patients, respectively, 16% with cirrhosis in the ION-1 and 20% with cirrhosis in the ION-2 study. Even if the low number of patients with cirrhosis included in the studies is taken into account, results showed that there was no significant difference in SVR12 rates among treatment-naïve patients with cirrhosis in any of the different arms (94–100%) and compared to patients without cirrhosis (97–99%). Cure rates in the 12-week arms were slightly lower in treatment-experienced patients with cirrhosis (86% without and 82% with RBV), while all patients with cirrhosis treated for 24 weeks achieved an SVR whatever the regimen. Similar promising results were reported in the COSMOS study assessing the effectiveness of SOF/SIM for 12–24 weeks with and without RBV.[24] In the small subgroup of treatment-naïve/experienced F3-F4 patients (n = 41) the SVR rate ranged from 85% in the 12-week arm to 100% in the 24-week arm, with no obvious impact of the addition of RBV. Overall, these studies showed that oral, IFN-free regimens were effective in patients with cirrhosis, and even suggested an improvement in some cases with longer duration regimens, even if they did not have enough power to identify subgroups of patients with lower SVR rates. The TURQUOISE-II study[16] was designed to assess the effectiveness of PAR/DAS/OMB plus RBV for 12 or 24 weeks in a large cohort of 380 treatment naïve or experienced patients with HCV-1 infection and cirrhosis with/without portal hypertension. This study was discussed recently.[25] SVR rates were 92% (97.5% CI 88–96%) at 12 weeks compared to 96% (CI 93–99%) at 24 weeks. Interestingly HCV-1a non-responder patients were identified as difficult to treat and achieved an SVR of 80% in the 12-week arm compared to 93% in the 24-week arm. This study further confirms that the results of IFN-free regimens are generally good in compensated patients with cirrhosis even if further clinical development is necessary in certain groups to improve SVR rates.

The real challenge of IFN-free regimes is treating patients with decompensated cirrhosis. This issue creates interesting avenues of research on antiviral effectiveness and clinical outcomes. At present there is no conclusive evidence on the effectiveness of antivirals in this difficult clinical setting. The only available recent data reported an SVR rate of 65% in 20 patients with HCV-1 decompensated Child B cirrhosis who received LED/SOF. The remaining 7 patients experienced a virological relapse.[26] These preliminary results must be confirmed and validated, even if they support the notion that the greater the severity of liver disease the lower the SVR rate in IFN-free regimens, probably because cirrhotic livers are less able to clear or cure infected cells. However, the other key issue in patients with decompensated cirrhosis is whether virological eradication can result in clinical improvement and compensated liver disease with possible removal from liver transplantation waiting lists, as observed in other clinical settings such as alcoholic hepatitis and HBV-related cirrhosis. Data are not available in this clinical setting where IFN is contraindicated, and where RBV can be a risk, and huge clinical advances are expected.

Existing evidence suggests that available and soon-to-be available IFN-free regimens are effective in patients with compensated cirrhosis, even if further clinical studies are necessary to identify difficult to treat patients (HCV-1a cirrhosis? cirrhotic non-responders?) requiring longer treatment and/or the addition of another DAA with/without RBV. On the other hand, data are needed in patients with decompensated cirrhosis, where the history of DAA-based regimens has barely begun.

Other areas of research in patients with cirrhosis are the use of RBV, and in particular, identifying clinical settings where RBV improves SVR, and finally, safety issues. Data on the safety of IFN-free regimens in patients with cirrhosis are only available for certain combinations and in patients with well-compensated disease. However, the impact of these drugs in patients with compensated cirrhosis – with older disease and co-morbidities – as well as in patients with decompensated liver disease must be evaluated.

Backup Strategies for Failure of DAAs: New Generation DAAs or IFN/RBV ?
The high number of HCV-1 patients treated with TVR or BOC-based TT in phase II and III clinical trials and then in clinical practice, has generated a corresponding proportion of patients with HCV variants resistant to NS3–4A protease inhibitors. With the introduction of IFN-based or IFN-free regimens with new generation DAAs the presence of patients with multidrug resistant viral populations is expected. Thus, the clinical relevance of response to other antiviral strategies has not been sufficiently studied and data are limited. However, the lower SVR rates observed in HCV-1a patients with the Q80K substitution treated with SIM-based therapy suggests that this issue must be carefully evaluated.[9,10]

Observational data on the failure of first generation PI have shown that viral populations resistant to NS3-4A protease inhibitors progressively decline, replaced by wild-type viruses within a few months after treatment withdrawal. These encouraging experimental results were confirmed clinically in a preliminary study showing high SVR rates in patients who did not respond to TVR or BOC TT when there were retreated with IFN-free regimens. Specifically, a 24-week course of SOF/DAC with/without RBV resulted in an SVR in 40/41 patients who failed TVR-based TT.[23] The LONESTAR-1 study[27] tested the effectiveness of 12 weeks of SOF/LED with/without RBV in 40 HCV-1 CHC patients who did not respond to first generation PI, 22 of them with cirrhosis. The authors reported SVR rates of 95% and 100% in the arms without and with RBV respectively.
Results in patients who did respond to IFN plus new generation DAAs vary. Nineteen HCV-1 patients from the ELECTRON-1 study who relapsed after SOF TT were retreated with 12 weeks of SOF/LED and all of them achieved an SVR.[26] On the other hand, HCV-1 patients who did not respond to PEG-IFN/RBV + an investigational PI with/without LED or tegobuvir, achieved an SVR rate of 74%.[28] Most of these patients (90%) carried at least 1 resistance associated variant.
Finally, clinical trials have shown that IFN-free regimens combining more DAAs are highly effective, and that virological failures because of breakthrough or relapse with resistant viruses are rare due to the high resistance barriers. Nevertheless, it should be remembered that: (i) viral populations harbouring resistance to NS5A protease inhibitors may persist for many years after treatment is discontinued and that the clinical significance of this is unknown for new combinations; (ii) the development of viral strains resistant to DAAs is expected to increase in clinical practice because of cases of suboptimal adherence to therapy; and (iii) until now studies evaluating escape strategies for unsuccessful IFN-free regimens have not been performed.

Although results are encouraging and suggest that IFN-free regimens are highly effective in cases of failure with BOC or TVR, further efforts are needed to identify standardized or personalized approaches in patients who do not achieve an SVR even with IFN-based or IFN-free new generation DAA combinations. For this, different approaches should be tested, such as careful assessment of virological strains, extending therapy, and/or adding PEG-IFN and/or RBV to modulate the immune system.

The issue of the cost: careful cost-effectiveness analyses needed
The rapid change in the landscape of antiviral therapy has resulted in an increase in the number of available molecules and significantly better results as well as a significant increase in the cost of drugs. Specifically, the cost of one course of antiviral therapy increased from approximately €10 000–15 000 for DT, to €30 000 for IFN-based first-generation PI therapy and €60 000 with SOF TT. In particular pricing of IFN-free regimens is not yet available, but the cost of the combination of SOF with SIM is approximately €120 000. This raises the key question of whether the application of a universal IFN-free strategy by national healthcare systems is viable in all HCV-1 CHC patients. To answer this question, assessment of the price of a course of antiviral therapy must take into account the cost of drugs, the effectiveness of the treatment strategy, and both direct and indirect costs of the management of side-effects related to drugs. In this way, we can accurately calculate the real cost of achieving an SVR. However, to assess the cost-effectiveness of a therapeutic strategy, its impact on the natural history of the disease and on the costs of managing the disease over time must also be evaluated. For this, the incremental cost-effectiveness ratio for life-years gained or for quality adjusted life years are the markers used. Two recent cost-effectiveness analyses of IFN-free regimens were published for CHC patients with contrasting results.[29,30] Differences in the results of these analyses were due to the estimated pricing of IFN-free regimens and the different comparison arms. Younossi et al.[29] simulated an unrealistic scenario in which the price of the IFN-free regimen was the same as IFN-based first-generation PI which generated a universal cost-effectiveness of IFN-free therapy. On the other hand, Deuffic-Burban et al.[30] developed a more realistic model in which IFN-free treatment was twice as expensive as IFN-based second generation DAAs. This model resulted in the lack of cost-effectiveness of a full IFN-free scenario. However, although the proposed analyses are useful for decision-making and for negotiation of the price of newer IFN-free regimens, the clinical value and ethical impact of treatment should not be unduly influenced by an economic analysis. In other words, availability of highly effective, short duration well tolerated treatment regimens, make them preferable for all patients, from those with advanced disease to those with mild liver damage. Although pricing and cost-effectiveness analyses provide information on IFN-free cost-effectiveness in all clinical scenarios, they cannot determine which patients should receive IFN-free and IFN-based strategies. In resource-limited settings a priority-based treatment plan must be designed where patients at high risk of the complications of liver disease are treated first while those with milder disease can be deferred while undergoing periodic re-evaluation of liver damage.

The availability of short duration, safe and highly effective regimens has created new challenges in the treatment of patients with HCV infection, and especially in groups in which the SVR was low with prior therapies, or in which IFN-based strategies were contraindicated. Despite the optimism for the near future, certain areas require further evaluation to make IFN-free regimens effective in all patients. Finally, efforts should be made to make IFN-free cost-effective in all clinical scenarios and accessible to all patients.


Gilead Expands Hepatitis C Generic Licensing Agreements to Include Investigational Pan-Genotypic Agent

Gilead to Allow Generic-Drug Makers to Produce New Hepatitis C Treatment
Gilead Sciences Believes New Version Will Be More Effective at Treating Hepatitis C

Gilead Expands Generic Sovaldi Pact to Add Investigational Pill Gilead Sciences Inc. 
(GILD) said it aims to launch Sovaldi, its blockbuster hepatitis C drug, in India by June while expanding the reach of a generic licensing agreement with Indian drugmakers to include an investigational combination pill. The pill, which combines sofosbuvir, the chemical name for Sovaldi, with GS-5816, a compound in advanced clinical trials in the U.S., could treat six genotypes of hepatitis C if approved by regulators...

Press Release:
Gilead Expands Hepatitis C Generic Licensing Agreements to Include Investigational Pan-Genotypic Agent

-Sofosbuvir/GS-5816 Single Tablet Regimen May Provide Important New Option for Patients in Developing Countries -

FOSTER CITY, Calif.--(BUSINESS WIRE)--Jan. 26, 2015-- Gilead Sciences, Inc. (Nasdaq:GILD) today announced that the company has expanded its hepatitis C generic licensing agreements to include the investigational NS5A inhibitor GS-5816, which is being evaluated in Phase 3 clinical studies as part of a single tablet regimen that combines the compound and sofosbuvir for the treatment of all six genotypes of hepatitis C. The expanded agreements will allow Gilead's India-based partners to manufacture GS-5816 and the single tablet regimen of sofosbuvir/GS-5816, once approved, for distribution in 91 developing countries, which together account for 54 percent of the total worldwide population of individuals infected with the hepatitis C virus (HCV).

If approved by regulatory authorities, the sofosbuvir/GS-5816 regimen would become the first pan-genotypic, all-oral single tablet regimen for HCV. A pan-genotypic therapeutic option is particularly important for developing countries, where genotype testing is often unreliable or not readily available.

"Today's announcement marks an important milestone in Gilead's effort to make effective hepatitis C treatment accessible to as many patients, in as many places, as quickly as possible," said Gregg H. Alton, Executive Vice President, Corporate and Medical Affairs, Gilead Sciences. "Developing countries are home to a diverse mix of hepatitis C genotypes, and the development of a medicine that has the potential to cure any patient, regardless of genotype, could help accelerate access to treatment."

Professor Abhijit Chowdhury, Head of Hepatology, Institute of Post Graduate Medical Education and Research, Kolkata, commented: "Pan-genotypic hepatitis C treatments have the potential to radically change the treatment landscape in developing countries, removing the need for patients to undergo burdensome laboratory tests. Even if testing facilities are available, their cost is a barrier to treatment access, so a regimen that can be used for any genotype is going to be a real attribute in tackling this disease on a global level."

The amended agreements expand on Gilead's existing generic licensing partnerships for hepatitis C, announced in September 2014, under which partners may produce sofosbuvir and the single tablet regimen of ledipasvir/sofosbuvir. Eight Indian-based generic manufacturers now hold licenses to manufacture Gilead's HCV medicines - Biocon Ltd., Cadila Healthcare Ltd., Cipla Ltd., Hetero Labs Ltd., Mylan Laboratories Ltd., Ranbaxy Laboratories Ltd., Sequent Scientific Ltd. and Strides Arcolab Ltd.

Sofosbuvir recently received regulatory approval in India (January 2015), and regulatory submissions have been completed in additional countries, including Pakistan, Thailand, Brazil, Uganda, South Africa and Nigeria.

About GS-5816

The single tablet regimen of sofosbuvir/GS-5816 is an investigational agent and its safety and efficacy have not been established. Phase 3 studies evaluating the combination of GS-5816 and sofosbuvir are currently underway, with data anticipated in the second half of 2015.

Gilead's Approach to Treatment Access in Developing Countries

Gilead makes it a priority to increase access to its medicines for people who can benefit from them, regardless of where they live or their economic means. In developing countries, Gilead's treatment access strategies include tiered pricing, voluntary generic licensing (often in advance of U.S./EU regulatory approval), negotiation with national governments, regional business partnerships, product registration, medical education and partnerships with non-profit organizations. This approach has been successfully applied to Gilead's humanitarian program in HIV over the past 10 years, where seven million patients are now receiving Gilead-based HIV medicines in developing countries.

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. Gilead has operations in more than 30 countries worldwide, with headquarters in Foster City, California.

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 possibility of unfavorable clinical results on the single tablet regimen of sofosbuvir/GS-5816. Further, sofosbuvir/GS-5816 may not receive marketing approval by regulatory authorities. As a result, the generic licensing partners may not be able to produce and distribute generic versions of sofosbuvir/GS-5816. 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 September 30, 2014, 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.

For more information on Gilead Sciences, please visit the company's website at, 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)
Nick Francis, 650-522-5674 (Media)

Sunday, January 25, 2015

HCV Weekend Video - Basic facts on hepatitis C

HCV Weekend Video:

Basic facts on hepatitis C 

Good morning everyone, today we have two videos offering basic information on hepatitis C and the liver. Topics range from transmission, testing, to new treatments. 

Hepatitis C 
Uploaded by Gastrointestinal Society

Updated To Include Press Release - Feb 10 2015
Gastrointestinal Society Releases New Video about Hepatitis C

Published on Jan 20, 2015
Hepatitis C is a liver disease caused by the Hepatitis C virus, this video discusses screening, symptoms, treatments, and more about this curable disease.

For more free information on this and other digestive diseases and disorders the Society covers, please visit our website

Chronic Hepatitis C
Uploaded by Rajmuf
Published on Jan 17, 2015

Detailed Overview: Transmission, testing, management, and new treatments. 

Sofosbuvir-based regimens for HCV: SVR12 Is Equivalent to SVR24 in Assessing New HCV Regimens

Related Video Podcast: Jan 16 2015
AASLD Video Podcast: Concordance of Sustained Virological Response With Sofosbuvir-containing Regimens for HCV

Full text available; Concordance of sustained virological response 4, 12, and 24 weeks post-treatment with sofosbuvir-containing regimens for hepatitis C virus 

NEJM Journal Watch 
January 23, 2015

SVR12 Is Equivalent to SVR24 in Assessing New HCV Regimens

Atif Zaman, MD, MPH reviewing Yoshida EM et al. Hepatology 2015 Jan.

The two efficacy endpoints were highly concordant in data from phase III trials of sofosbuvir-based regimens.

Eradication of hepatitis C virus (HCV) is typically defined as an undetectable level of HCV RNA 24 weeks after completing treatment (i.e., sustained virologic response at week 24, or SVR24). The FDA recently determined that sustained virologic response at 12 weeks posttreatment (SVR12) is as valid as SVR24 as an efficacy endpoint due to its high rate of concordance with SVR24. However, this concordance has not been extensively studied since the advent of direct-acting antiviral–based regimens.

In a retrospective analysis of data from five phase III trials of sofosbuvir-containing regimens (with and without peginterferon) in 863 patients with HCV infection (genotypes, 1–6), investigators assessed the concordance between SVR at 4 weeks (SVR4) and SVR12, concordance between SVR12 and SVR24, and positive-predictive and negative-predictive values (PPV and NPV).

Rates of SVR4, SVR12, and SVR24 were 92%, 91%, and 91%, respectively, in patients with HCV genotype 1 or 4 through 6; 94%, 92%, and 92% for genotype 2; and 87%, 85%, and 84% for genotype 3. The concordance of SVR4 and SVR12 was 98% (PPV, 98%; NPV, 100%). The concordance of SVR12 and SVR24 was >99% (PPV, >99%; NPV, 100%). Over three fourths (78%) of patients who relapsed post-therapy did so within the first 4 weeks.

This analysis of data from phase III trials of sofosbuvir-based regimens for HCV infection confirms that SVR12 is equivalent to SVR24 as an efficacy endpoint. This is true for direct-acting antiviral regimens that include interferon and for interferon-free regimens. In clinical practice, SVR12 can routinely be used as a marker for treatment success among HCV monoinfected patients with compensated liver disease. Further analysis should be forthcoming regarding special subpopulations such as patients who are coinfected or have decompensated liver disease.

Disclosures for Atif Zaman, MD, MPH at time of publicationNothing to disclose

Yoshida EM et al. Concordance of sustained virological response 4, 12, and 24 weeks post-treatment with sofosbuvir-containing regimens for hepatitis C virus. Hepatology 2015 Jan; 61:41. (
PubMed abstract (Free)

Saturday, January 24, 2015

German insurers win discounts on Gilead's Sovaldi

German insurers win discounts on Gilead's Sovaldi

FRANKFURT (Reuters) - U.S. biotechnology company Gilead (GILD.O) has conceded its first discounts in Germany on its key hepatitis C drugs Sovaldi and Harvoni, German business weekly WirtschaftsWoche reported.

The head of Gilead's German operations told the magazine that discounts from the list price of 60,000 euros (44,867 pounds) per treatment had been negotiated with four of Germany's statutory health insurers but declined to give the size of the discounts.

"Thirty-five percent of people with statutory health insurance are already profiting from the discount agreements," Carsten Nowotsch said in an interview to be published on Monday, adding that more such contracts could follow.

Germany is Europe's biggest market for medicines, and dozens of healthcare agencies in Europe and as far away as Japan use German prices as references for their own.

Solvadi was the first effective cure for hepatitis C on the market and quickly amassed billions of dollars in sales within its first few months on the market in 2014.

Last month, U.S. regulators approved a competing treatment from AbbVie (ABBV.N), immediately prompting the country's largest pharmacy benefits manager Express Scripts (ESRX.O) to drop reimbursement for the Gilead drug.

Gilead received regulatory approval for its newer hepatitis C drug, Harvoni, last October.

($1 = 0.8923 euros)

(Reporting by Georgina Prodhan, editing by David Evans)
Source - Reuters

Reducing the cost of new hepatitis C drugs
An index of articles pointing the reader to the current controversy over the high price of Sovaldi, Harvoni (ledipasvir/sofosbuvir) and AbbVie Viekira Pak.



Wednesday 21 January 2015

Researchers at the Hubrecht Institute and the University Medical Center (UMC) Utrecht successfully developed a culturing system for human liver stem cells as well as stem cells from pancreatic cancer. They describe the development of these culturing systems in two articles in this week’s edition of Cell magazine.

Until recently it appeared impossible to keep healthy or diseased tissue from patients alive under laboratory conditions, let alone multiply it. However, in 2009, the research group headed by Hans Clevers, professor of molecular genetics at the Hubrecht Institute/UMC Utrecht and president of the Royal Dutch Academy of Arts and Sciences (KNAW), described a revolutionary culturing method that allowed the culturing of mini-guts from single mouse intestine stem cells. These organoids are functional miniature organs that can grow in tissue culture. The same research group now adds a culturing system for liver stem cells and stem cells from pancreatic cancer to their record. In the future, cultured stem cells could conceivably replace donor organs for transplantation. They also offer prospects for research into 'personalized medicine', the prescription of medication specifically geared to individual patients.

The technology described in Cell can be used for the long-term replication in the laboratory of minute amounts of tissue harvested from a healthy or diseased liver. Over a period of four months, the equivalent of a full-grown liver can be cultured from a single liver stem cell. All analyses show that this cultured tissue is genetically the same as healthy liver tissue and is very stable as well.

The cultured human ‘mini-livers” have already been successfully transplanted in mice with liver damage. This is the first step towards using this cultured liver tissue to replace donor livers for transplantation. As such, this technology could solve the world-wide shortage of donor livers. Moreover, this technology offers future potential for personalized medicine. Organoids could, for instance, be grown from the tissue of patients suffering from genetic liver diseases, so that drugs can be tested on this patient material first before being administered to the patient themselves. Examples of such diseases are alpha-1 antitrypsin deficiency and Allagile syndrome.

Hans Clevers’ research group additionally reports on a technology for the long-term laboratory culturing of healthy and diseased pancreatic stem cells, which was not possible before. To this end, the group worked with one of the world’s leading lights in the field of pancreatic cancer, David Tuveson of Cold Spring Harbor Laboratory in New York.

The study in Cell shows that the sensitivity or resistance of the tumor tissue of individual patients to a wide range of cancer drugs can be determined in the laboratory. As a next step, this method can therefore be used to prescribe individualized therapy for each cancer patient.

The technology described was then used to create a ‘Living Biobank’ of cultured pancreatic tumors from a large group of patients with pancreatic cancer. This allows the culturing of organoids from multiple patients, which in turn makes it possible to study larger populations. Established with support from the Dutch Cancer Society/Stand up to Cancer, this biobank is open to cancer researchers and companies worldwide wanting to develop new cancer drugs and treatments.

Pancreatic cancer is one of the deadliest forms of the disease: only 6% of patients survive for over 5 years. There is no effective therapy for pancreatic cancer at the moment.

The Hubrecht Institute is the KNAW’s research institute and has been affiliated with the UMC Utrecht since 2008.


Huch M, Gehart H, Boxtel R van, Hamer K, Blokzijl F, Verstegen MMA, et al. Long-term culture of genome-stable bipotent stem cells from adult human Liver. Cell 2014, doi: 10.1016/j.cell.2014.11.050

Boj SF, Hwang C-I, Baker LA, Chio IIC, Engle DD, Corbo V, et al. Organoid models of human and mouse ductal pancreatic cancer. Cell 2014, doi: 10.1016/j.cell.2014.12.021

Key role for Hep C Inquiry- By 2030 there should be no deaths in Australia related to hepatitis C

Key role for Hep C Inquiry
Angus Morgan
23 January, 2015

Burnet’s Professor Margaret Hellard says the Federal Parliamentary Inquiry into hepatitis C has a key role to play in the development of a strategy for the elimination of the disease in Australia.

The Inquiry, conducted by the House of Representatives Standing Committee on Health, was in Melbourne on Wednesday for the first of two round table hearings with support services and medical experts on testing and treatment options.

Professor Hellard, Head, Centre for Population Health at Burnet Institute, told the hearing that hepatitis C, which affects more than 230,000 Australians, could be eliminated by 2030.

“To do this we need to take a strategic approach which requires a combination of harm reduction, opiate substitution therapy, needle and syringe programs, both in the community and correctional settings,” Professor Hellard said.

“Then there’s treatment, which is required for people who have significant liver disease.”

“We are at a time in history which is unusual for infectious diseases in the sense that we have a cure for hepatitis C; the new drugs that are available make that possible.

“It means that people with significant liver disease, stage 3 and 4, what we call fibrosis, can be cured, and so people should not be dying of this disease.

“By 2030 there should be no deaths in Australia related to hepatitis C.”

Professor Hellard said the effective treatment of the transmitters of infection – predominantly, people who inject drugs – is a critical part of the strategy.

“If we use these treatments wisely, we can turn off the tap of infection, and we can ensure that by 2030 we’ve reduced transmission of hepatitis C so that it’s no longer a significant health issue for Australia,” she said.

“These things are possible, but we need our politicians to be brave, we need them to be wise, we need them to be bold.

“We need ‘hepatitis heroes’ amongst our leaders in the political arena so that we can solve this health problem for Australia and show leadership globally around how to solve the hepatitis C problem.”

Professor Hellard said she believes she and other Inquiry stakeholders, including Hepatitis Victoria, the Australasian Society for Infectious Diseases, the Australian Liver Association and Haemophilia Foundation Australia, were well received.

“I think the Committee came away much better informed about hepatitis C and the key issues that need to be addressed to reduce the impact of this virus which is leading to significant deaths in Australia,” Professor Hellard said.

“It’s my hope that we will come up with a strategic plan and vision for the elimination of hepatitis C in Australia.”

The Inquiry conducted its second round table hearing in Sydney on Thursday ahead of the deadline for written submissions at the end of February.


Friday, January 23, 2015

Neuroimaging abnormalities, neurocognitive function, and fatigue in patients with hepatitis C

Neuroimaging abnormalities, neurocognitive function, and fatigue in patients with hepatitis C

April D. Thames, PhD, Steven A. Castellon, PhD, Elyse J. Singer, MD, Rajakumar Nagarajan, PhD, Manoj K. Sarma, PhD, Jason Smith, PharmD, Nicholas S. Thaler, PhD, Jonathan Hien Truong, MD, Daniel Schonfeld, BS, M. Albert Thomas, PhD and Charles H. Hinkin, PhD

Published online January 14, 2015 doi: 10.1212/NXI.0000000000000059Neurol Neuroimmunol Neuroinflamm February 2015 vol. 2 no. 1 e59

Objective: This study examined neurologic abnormalities (as measured by proton magnetic resonance spectroscopy imaging and diffusion tensor imaging), neurocognitive performance, and fatigue among a sample of adults with hepatitis C virus (HCV). We hypothesized that HCV+ individuals would demonstrate structural brain abnormalities and neurocognitive compromise consistent with frontostriatal dysfunction as well as increased fatigue compared to controls.

Method: Participants were 76 individuals diagnosed with HCV and 20 controls who underwent a comprehensive neurocognitive evaluation and clinical assessments. A subset of the HCV+ participants (n = 29) and all controls underwent MRI.

Results: Individuals diagnosed with chronic HCV infection demonstrated greater fractional anisotropy in the striatum as well as greater mean diffusivity in the fronto-occiptal fasciculus and external capsule compared to HCV− controls. HCV+ participants also demonstrated lower levels of N-acetylaspartate in bilateral parietal white matter and elevations in myo-inosital (mI) in bilateral frontal white matter compared to HCV− controls (all p values < 0.05). HCV+ participants also demonstrated significantly poorer neuropsychological performance, particularly in processing speed and verbal fluency. HCV+ patients reported higher levels of fatigue than controls, and fatigue was significantly correlated with diffusivity in the superior fronto-occipital fasciculus, elevations in mI in frontal white matter, and overall cognitive performance.

Conclusions: Our results suggest that HCV-associated neurologic complications disrupt frontostriatal structures, which may result in increased fatigue and poorer cognitive performance, particularly in those cognitive domains regulated by frontostriatal regions.

View full text online
Download PDF

The current study examined the effects of chronic HCV infection on microstructural brain abnormalities, cerebral metabolites, fatigue, and neurocognitive performance. Major strengths of the current investigation include the use of DTI and MRSI in combination with measures of neurocognitive functioning and fatigue, and the use of a control group for comparison. As hypothesized based on prior literature, we observed microstructural abnormalities in such areas as the striatum, external capsule, and fronto-occipital fasciculus, which is consistent with previous DTI studies of HCV9,10 and findings among individuals with HIV infection.28,29

We observed greater FA in gray matter regions of the striatum in HCV+ patients compared to healthy volunteers. Higher FA in the striatum has been found among patients with Huntington disease32 and is thought to be due to degeneration of efferent pathways that increase the coherence of gray matter structures. In a study of patients with chronic subdural hematoma, increased FA was found in the striatum, which reduced following surgical intervention.33 Therefore, our findings are consistent with other investigations of neuropathology in regions that are affected in HCV.

Increased diffusivity in the fronto-occipital tract and external capsule was also found in the HCV+ group compared to controls. The fronto-occipital tract has been suggested as modulating frontal lobe–related inhibitory control and occipital lobe–related sensory inputs.34 Alterations of this tract may interfere with integrating sensory information and inhibiting control over impulses and emotion, which is problematic among drug abusers. The external capsule contains a variety of different nerve bundles and pathways connecting the cerebral cortex to subcortical nuclei as well as connecting different parts of the cortex to each other. Therefore, disruption to fibers of the external capsule may result in dysfunction of frontal-subcortical circuitry.

HCV+ participants demonstrated lower levels of NAA in bilateral parietal white matter and elevations of mI in bilateral frontal white matter compared to controls, which was associated with poorer performance in the cognitive domains of processing speed and verbal/language fluency. Further, there was a correspondence between our DTI and MRSI measures. Specifically, higher NAA in parietal white matter was significantly correlated with lower diffusivity in the fronto-occipital fasciculus, whereas greater frontal white matter mI was significantly correlated with higher diffusivity in the fronto-occipital fasciculus.

That stated, our MRSI results were generally consistent with previous MRSI studies of HCV+ cohorts,8,12,35 although we did not observe abnormal cerebral metabolite levels in basal ganglia as was expected.

However, in the current study we were careful to exclude participants with medical (e.g., cirrhosis) and psychiatric conditions that potentially could have confounded interpretation of the neuroimaging findings. Through this process we may have excluded HCV+ individuals with more severe neurologic impairments and neuropathologic changes in subcortical structures that are detectable by H-MRS. Although HCV+ patients demonstrated poorer global neurocognitive performance than controls, examination of performance data suggests normal range of performance (i.e., T > 40). Again, because of the use of stringent inclusion/exclusion criteria, this group may not be fully representative of the general HCV+ population. Despite the potential recruitment of higher-functioning HCV+ individuals, we still found the poorer performance in the cognitive domains of processing speed and verbal fluency (relative to controls) that has been reported across other studies,4,5,13,15,16 and this performance was independent of such factors as liver fibrosis and history of substance abuse.

HCV+ participants also reported greater fatigue than controls, which was associated with abnormalities in frontal white matter, whereas poorer cognitive performance was associated with abnormalities in both frontal white matter and subcortical structures. These results suggest that HCV-associated neurologic complications that are specific to changes in frontal-subcortical structures give rise to both reduced cognitive performance and fatigue. The specific cognitive deficits observed in verbal/language fluency and information processing speed are all regulated by frontal-striatal structures.36 In our sample, verbal fluency demonstrated the greatest degree of performance difference between HCV+ and control groups and the strongest correlation with elevated levels of mI in frontal white matter.

There are limitations to the current study. First, while structural neuroimaging methods are helpful in identifying microstructural pathology that may not be detected on standard MRI, they do not provide a clear understanding about the functions of these neural circuits. Hence, existing disruptions in a neural circuit may make a patient more vulnerable to developing symptoms such as fatigue. Second, although we attempted to control for a number of demographic variables between HCV patients and controls, we recognize that there are a myriad of psychosocial differences (e.g., stress, past drug use) that may account for the reduced cognitive performance and structural brain differences that were observed in the current study. For instance, we were unable to examine past drug abuse differences between our HCV+ and control groups because information on past drug abuse was not collected from the controls. We recognize that in order to precisely rule out the effects of past drug abuse we would have needed to recruit a sample of past drug abusers who were HCV−. However, considering that 61% of our HCV+ patients reported a lifetime history of cocaine or opiate use, we attempted to address this concern by examining the effects of past drug abuse within this subgroup. While we did not find significant differences in our neuroimaging or neurocognitive data as a function of past drug abuse (all p values > 0.10), we cannot rule out the residual confounding effects of distant substance use on neurologic function.

Despite these limitations, the current study represents a significant extension of the extant literature on HCV's effects on neurologic and neurobehavioral functioning by demonstrating how abnormalities in frontal/parietal and subcortical structures have independent and overlapping relationships with cognitive performance and fatigue.

It has long been known that HCV is hepatotoxic; increasingly there is reason to believe that it is neurotoxic as well. While the precise pathophysiologic mechanism remains unclear, findings from the current study as well as others have demonstrated that HCV infection is associated with neurophysiologic and neurobehavioral abnormality. While advances in the pharmacologic treatment of HCV hold incredible promise, there remain millions of HCV-infected adults in the United States and approximately 100 million worldwide. Continued study of the neurologic effects of HCV is needed. 

Navigate This Article

Thursday, January 22, 2015

Express Scripts' Miller says hepatitis C price war to save billions

Express Scripts' Miller says hepatitis C price war to save billions
NEW YORK Thu Jan 22, 2015 11:12pm IST

(Reuters) - Gilead Sciences Inc and AbbVie Inc are in a price war over their hepatitis C treatments that is driving costs lower and has changed the way drugmakers price new medicines, a top executive for pharmacy benefit manager Express Scripts said on Thursday.

Gilead's hepatitis C drug Harvoni, which can cure a majority of patients who take it, has a retail price of $94,500 and is now facing its first competition with AbbVie's Viekira Pak, which was priced about $10,000 lower, or at $83,319.

Express Scripts was able to secure a discount that has brought the AbbVie price down to Western European levels for Gilead's hepatitis C treatment, Chief Medical Officer Steven Miller told Reuters. Such prices overseas range from about $51,000 to $66,000.

The gap in price between Harvoni and Viekira has stayed about the same as both have fallen, Miller said.

The dynamic will save Express Scripts customers $1 billion in 2015, with a total of $4 billion in savings across the United States when all payers and employers are included, Miller said. He expects over 170,000 people will be treated for the liver-destroying virus in the United States in 2015, up from 100,000 last year.

"This is the first time in the history of the pharmaceutical industry that someone has been able to create a price war," Miller said in an interview.

Gilead set off a national debate about the affordability of drugs last year after it priced its new hepatitis C drug Sovaldi at $84,000 per treatment, or about $1,000 per pill. That drug has been followed by a combination pill that is more expensive called Harvoni.

An estimated 3.2 million people in America have the virus, and many health insurers and payers said the cost of treating all of them would be unaffordable.

Express Scripts Holding Co, the nation's largest pharmacy benefits manager, has been the most vocal critic of Gilead for its pricing. When U.S. health regulators approved AbbVie's Viekira Pak in late December, Express Scripts announced within days that it was dropping coverage of Gilead's treatments from its largest list of reimbursable drugs, except under certain medical exceptions.

Express Scripts and its clients are reaping new savings as prices head lower from both Gilead and AbbVie, but that will not change Harvoni's place on its reimbursement list in the near future.

"They cannot buy their way back onto the national preferred formulary at this time," Miller said of Gilead. Express Scripts' agreement with AbbVie spans multiple years but Miller declined to say how many.

Beyond hepatitis C, other drugmakers are showing much more willingness to discuss pricing early on in the development of new treatments, Miller said. That includes more detailed talks on how many patients would most benefit from a new therapy.

The industry is closely watching two new areas to see how the pricing dynamics will play out - PCSK9s for high cholesterol and PD-1s for cancer.

"More companies are coming to us, telling us about their pipeline and wanting to know what kind of data we want to see," Miller said.

(Reporting by Caroline Humer and Michele Gershberg; Additional reporting by Bill Berkrot; Editing by Christian Plumb)

Researchers unravel complicated relationship between diabetes and HCV

Researchers unravel complicated relationship between diabetes and HCV

The relationship between diabetes and hepatitis C virus is a complicated one. Despite years of research involving a host of studies and meta-analyses, the clinical community has failed to reach a consensus on the nature of the association between the two diseases.

Some research suggests that curing HCV would reduce the likelihood of developing diabetes, that controlling diabetes would improve HCV outcomes, and that adequately treating one condition would allow the other to be more manageable. In conflict with those studies, recent data published in Hepatologysuggested no association between HCV and diabetes.

“The link between HCV and diabetes is multifactorial and not completely understood,” Salvatore Petta, MD, PhD, specialist and lecturer in gastroenterology at the University of Palermo, Italy, said in an interview.

Uncertainty aside, Endocrine Today interviewed leading experts about the link between HCV and diabetes, the current evidence base, treatment options and what is needed in the future to fully understand this association.

New machine-perfusion organ preservation system keeps livers healthier for transplant

New machine-perfusion organ preservation system keeps livers healthier for transplant

PITTSBURGH, Jan. 22, 2015 - A new preservation system that pumps cooled, oxygen-rich fluid into donor livers not only keeps the organs in excellent condition for as long as nine hours before transplantation, but also leads to dramatically better liver function and increases survival of recipients, according to a series of animal studies by researchers at the University of Pittsburgh School of Medicine and the McGowan Institute for Regenerative Medicine. The system could be tested with transplant patients at UPMC later this year.

The findings, which were published online in the American Journal of Transplantation, suggest that it's possible to use the technique of "machine perfusion" with a newly created cell-free oxygenated solution to expand the number of high-quality livers available for transplant, thereby shortening waiting times and reducing patient mortality.

Currently, 20 to 40 percent of donor livers cannot be transplanted into recipients because oxygen deprivation during storage and transport in conventional containers can make pre-existing tissue damage worse, explained senior investigator Paulo Fontes, M.D., UPMC transplant surgeon, associate professor, Starzl Transplantation Institute, Department of Surgery, Pitt School of Medicine, and a deputy director of the McGowan Institute. If the damage is too extensive, the organ cannot be safely transplanted into a patient.

"Standard practice is to use a method called cold static preservation, which uses tissue cooling to slow down metabolism with the aim of reducing the demand for oxygen and thus protecting cells from death," Dr. Fontes explained. "In our new system, we pump a special fluid designed to deliver oxygen to the liver, creating an environment that supports normal function. The integrity of the cells and vital metabolic activity is sustained for eventual transplantation of the organ."
The research team optimized a machine-perfusion (MP) device that was developed by Organ Assist, a company in the Netherlands, and added a fluid with a hemoglobin-oxygen carrier component to deliver high concentrations of oxygen to the tissue. The liver is immersed in chilled fluid, which is also pumped through tubes inserted into the organ's large blood vessels to effectively oxygenate the tissue.

The team transplanted six pigs with livers that had been kept for nine hours, roughly the average time between recovery of the organ and transplantation into a recipient, in the MP system and another six with organs placed in the standard container.

They found that 100 percent of the pigs who got MP livers survived, compared to 33 percent of those who received conventionally preserved organs. The MP livers functioned better, produced more bile and had higher oxygen levels than their conventional counterparts, and analyses of multiple biomarkers including inflammatory mediators indicated that the MP livers had been better preserved.
Also, "it was immediately obvious to us that the pigs who received MP livers looked much healthier and easily moved around their pens just hours after they woke up from the surgery," Dr. Fontes said. "They didn't look as ill as the animals treated with standard cold preservation. It was amazing."
The data from the studies have been shared with federal regulators, he added, with the aim of launching a clinical trial to test the system at UPMC this year.

"This system has great potential to enhance our current standards for organ preservation, which should translate into more patients getting a life-saving procedure with potentially better outcomes," Dr. Fontes said. "Not only that, we have hopes of a faster recovery because the liver could be less likely to become injured due to a lack of oxygen."


Co-investigators include Roberto Lopez, M.D., Yoram Vodovotz, Ph.D., Marta Minervini, Ph.D., Victor Scott, M.D., Kyle Soltys, M,D., Sruti Shiva, Ph.D., Shirish Paranjpe, Ph.D., David Sadowsky, Derek Barclay, Ruben Zamora, Ph.D., Donna Stolz, Ph.D., Anthony Demetris, M.D., George Michalopoulos, M.D., Ph.D., and James Wallis Marsh, M.D., all of the University of Pittsburgh; and Arjan van der Plaats, Ph.D., of Organ Assist, Groningen, Netherlands.
The study was funded by a charitable gift from Mr. and Mrs. Garcia de Souza, as well as grant DK072146 from the National Institutes of Health.

About the University of Pittsburgh School of Medicine
As one of the nation's leading academic centers for biomedical research, the University of Pittsburgh School of Medicine integrates advanced technology with basic science across a broad range of disciplines in a continuous quest to harness the power of new knowledge and improve the human condition. Driven mainly by the School of Medicine and its affiliates, Pitt has ranked among the top 10 recipients of funding from the National Institutes of Health since 1998. In rankings recently released by the National Science Foundation, Pitt ranked fifth among all American universities in total federal science and engineering research and development support.
Likewise, the School of Medicine is equally committed to advancing the quality and strength of its medical and graduate education programs, for which it is recognized as an innovative leader, and to training highly skilled, compassionate clinicians and creative scientists well-equipped to engage in world-class research. The School of Medicine is the academic partner of UPMC, which has collaborated with the University to raise the standard of medical excellence in Pittsburgh and to position health care as a driving force behind the region's economy. For more information about the School of Medicine, see