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The Future of Liver Transplants

Wednesday, May 15th, 2013

In March I shared a startling statistic – the number of unusable donated livers is going up, mainly due to the increase of donor obesity rates and number of cardiac deaths (you can read the full blog post here). This month we are focusing on the good news – specifically the advancements of automated liver perfusion devices and artificial livers.

Researchers in England have been working on the technology for an automated liver perfusion device since 1994, and just recently successfully transplanted two livers. This device changes the way a liver is stored between the time it is taken out of the donor and transplanted into the patient. Currently the liver is kept on ice, cooling the organ and slowing down the metabolism. This method has been used for decades, however it can lead to the liver becoming damaged and unfit for use as it is risky to keep a liver on ice for over 14 hours.

Automated Liver Perfusion Device

The automated liver perfusion device works in the opposite way by preserving the organ at body temperature and perfusing it – keeping oxygenated red blood cells running throughout. The liver can function normally, with blood circulating and bile production, for over 24 hours outside of the body.

With two transplants already a success, the team of doctors, engineers and surgeons plans to run a pilot trial with 20 more transplants at King’s College Hospital in London. Upon completion of a successful trial, the team will then apply for marketing authority with hopes of getting the device on the market by 2014.

Bio-artificial Liver

Vital Therapies has entered phase 3 studies of their bio-artificial liver, the Elad. This cell-based liver is designed to stabilize liver function while the patient’s own liver heals itself, as the liver is able to regenerate damaged cells. Therapy lasts three to five days and involves the patient’s plasma going through the device which uses human liver cells to filter toxins and synthesize proteins and then returning the plasma to the patient’s bloodstream.

The Elad has not been without its struggles, as two companies have gone bankrupt while developing it. Artificial livers have been the focus of many institutions’ research, however this is the first device to reach phrase 3. Phase 3 trials are expected to be completed by the end of 2015. If successful the device could launch by the end of 2016.

Growing Liver from Stem Cells

In more futuristic liver advances, a liver bud has been grown from stem cells in Japan. The five millimeter bud was able to break down drug compounds, however it lacked bile ducts and did not produce as much albumin, a vital plasma protein, as needed for human liver function. Still, researchers are calling this study groundbreaking, with the ability to grow a functional human liver possible in the distant future.

3D Bioprinted Liver

Organovo announced at the Experimental Biology conference last month that they successfully created 3D bioprinter liver tissue. A 3D printer built up 20 layers of the two major types of liver cells – hepatocytes and stellates – to create in-vitro mini-livers that can perform many basic liver functions. Cells from the lining of blood vessels were also added, allowing the mini-livers to live for five or more days.

Creating a transplantable 3D printed liver is more than a couple years off; one of the biggest challenges will be to print the large branched networks of blood vessels needed by the liver. But in the meantime, the mini-livers can be used in labs to test the toxicity of drugs. Hepatocyte cells can replicate almost limitlessly inside the body, however,until now, there was no way to replicate them outside the body without losing some of their critical functions – essential for drug testing. Like the stem cell livers, 3D printed livers are poised to become a potential organ transplant game changer.

“The Silent Pandemic” Summary

Monday, February 25th, 2013

Last month the Economist Intelligence Unit (supported by Janssen) released the most comprehensive, worldwide HCV report that we have seen to date. We highly recommend anyone involved with HCV to read the full report here, however if you do not have the time/patience to read the full 20 pages we have highlighted the main points below. Stay tuned for our take on the report in an upcoming blog!

“The Silent Pandemic”

Tackling Hepatitis C with Policy Innovation

 Part 1: An iceberg looming in a fog of uncertainty

A big problem…

  • Hep C (HCV) called “the silent pandemic” as virus takes long time to manifest itself
  • 60-70% of those with HCV develop chronic liver disease
    • 20-30% develop cirrhosis, typically after two or three decades
      • As low as 10% for people infected when younger & healthier
    • Higher than normal risk of developing hepatocellular carcinoma (HCC), most common type of liver cancer
  • Healthcare costs of “end-stage” conditions can be substantial
    • Average liver transplant cost $139,000
      • 20% on transplant list die
      • Infection of new liver with HCV is inevitable
  • Disease prevalence higher in developing countries
    • Egypt has highest infection rate, about one in five
  • Rapid spread of disease prior to 1989, and time end stage conditions take to appear, means cirrhosis and liver cancer will become more common
    • In U.S. total number of cases will drop 24% between 2005 and 2021, but number of deaths will rise because of increase in mortality rates
  • In Egypt, liver cancer deaths rose from 4% to 11% between 1993 and 2009
    • U.S. deaths attributed to HCV rose by 50% between 1999 and 2007
      • Bigger killer in America than HIV
    • “For Hepatitis C in Europe, we expect a peak of those who develop end-stage status in 10 – 15 years” – Achim Katz, manager Deutsche Leberhilfe

…of undetermined size

  • Current HCV data poor & probably understate the problem
  • Few countries have tried to obtain even the most basic prevalent information
    • Within EU, only Netherlands has good data on HBV & HCV
      • 16 EU countries data poor or non-existent
    • Worse in Latin America & Africa
    • In Asia-Pacific region,only China, Australia & India have reasonable data
      • “In Asia there are countries where we don’t even have estimates of how many people are infected” – Jack Wallace, executive member of the Coalition for the Eradication of Viral Hepatitis in Asia and the Pacific

Good news and bad news

  • Combination therapies improving cure rate including those with genotype 1 (most common type in Europe & North America)
    • Cure rates up to 80% of cases, depends on factors including genotype, disease progression, how soon after infection treatment occurs, and existence of any co-morbidities
  • Therapy both expensive & complex, less viable option for developing nations
    • In wealthier countries with health systems with necessary expertise and resources, treatment is cost-effective
  • Therapies frequently not used, even when healthcare providers can do so
  • HCVwill bring economic burden in terms of lost work years
    • Cost of sick days and lower productivity per HCV- infected employee was $8,352/year

Part 2: Barriers to tackling HCV

  • Takes time for medical science to understand & development treatment, healthcare system to adjust & general public to become aware of the danger

Still much to learn

  • Not til 2012 that team could explain exactly how the virus used the liver to replicate itself
    • Some basics still unclear – why some reach end-stage conditions & others do not develop chronic HCV at all
  • Drug development – from identification of a promising molecule to drug approval – takes at least a decade
  • Healthcare systems notoriously slow at change and healthcare professionals frequently lack ability to treat (or even recognize) HCV
    • 31% of family physicians were uncertain what to do in the event of a positive test
    • Physicians with more than 20 years of experience were worst informed, physicians with fewer than 5 years were most informed
  • Lack of trained specialists who can administer treatments found in Australia, Germany & U.S.
  • Success against hepatitis B in 1990s can lead to complacency among policymakers about HCV
    • General public confuse hepatitis A, B, C and D – think vaccinated against all
  • Only 20% of Australian public thought HCV could cause cancer

Playing the odds in a dangerous game

  • Why so few patients are treated? Barriers at every level
  • Current drug regimen is complex with substantial side effects, both physical and psychological
  • Current therapy is expensive
    • Out of reach for many developing countries
  • Speed of scientific developments delaying patients from receiving treatments
  • Cost & inability to determine whowill develop complications are restricting use of medication
    • Some doctors ask patients with lower risk to wait for better therapy with few side effects
  • Existing treatments work better in early stages

See no evil

  • More difficult set of problems from perceptions of the disease
    • Developed countries transmission now highest among people who inject drugs (PWIDs)
      • Their link has attached stigma to HCV
  • 63% of world’s roughly 16M PWIDs have HCV
  • PWIDs more likely to be homeless or live in sub-standard housing, have other physical or psychological conditions & be economically worse off
    • Makes them imperfect patients for physically demanding, complex therapies
  • PWIDs and healthcare professional frequently mistrust each other
  • Stigma of disease has implications at government level
    • Some politicians feel more comfortable inserting HCV activities into existing programs
  • Easy to identify high risk behavior for transmission, long time it takes for complications to develop means this identification does not really help predict where worse problems will appear

Part 3: Finding a way forward

  • Single, detailed HCV solution not practical
    • Different countries have different genotypes, transmission routes & resources available
  • Countries need a systematic approach
  • Comprehensive approach needs to include: obtaining data for evidence-based policy, raising awareness & creating partnerships, prevention, care & treatment

Piercing the fog

  • Lack of good data a problem, even in developed nations
  • U.S. originally followed risk-based approach for screening
    • Many infected long ago, don’t recall relevant activities
  • CDC recommended testing all Americans born between 1945 and 1965
    • Group accounts for 82% of infections
    • Cost-effective in long run
  • Not right approach for every country
    • U.S. recommendation positive effect beyond screening – media coverage wide and positive

Raising public (and political) awareness

  • WHO designated July 28 as World Hepatitis Day
    • One of only four disease with a day – along with malaria, tuberculosis & HIV
  • Campaign needs to raise awareness AND engage governments

Prevention: Healthier than treatment

  • Prevention core component of HCV strategy
    • U.S. incidences dropped by 85% after screeing of blood supply began in early 1990s
  • Prevention strategies not perfect
    • U.S. has seen 32 outbreaks in last decade related to poor infection control practices
    • In Europe, Luxembourg & Liechtenstein still do not screen blood or organ donors
  • In developing countries, unsafe health practices most common cause of HCV
    • Egypt needs to tighten up on blood safety & reuse of equipment
  • Prevention can be effective for cash-strapped countries
    • Improve training & compliance of healthcare workers
    • Stricter policies on reuse of medical supplies
      • Auto destruct syringes cost-effective
    • Screening blood cheaper than treatment
  • Primary prevention is not only type
    • Current therapies not universally effective
    • Need chronic liver disease management plan
      • No medication, information on lifestyle choices
  • Even low alcohol use increases likelihood of developing cirrhosis or HCC
    • High usage more than doubles risk, also brings on conditions quicker

Reaching and caring for patients where they are

  • Developed countries need to find & treat HCV patients, especially current & former PWIDs
    • Requires innovation as well as money
    • Find patients, not wait for them to find doctor
  • Netherlands set up website with interactive questionnaire to identify high risk individual
    • At-risk individuals could get free, anonymous blood test
      • Positive tests offered treatment
    • Successful as low-cost & newly identified HCV individuals from hard-to-reach populations
  • Western Australia created hepatology nurse practitioner (HNP) within the liver sector
    • Position created as patients faced long waiting lists to see experts
    • HNP can order tests, give diagnoses, prescribe drugs & refer patients as well as monitor treatment & adjust in light of any side effects
    • Positive results – wait times down & faster attention to side effects has led to fewer complications
      • Specialists can concentrate on more difficult cases
      • 98% patients satisfied with HNP service

Gilead Sciences 100% Cure Rate for HCV

Wednesday, November 14th, 2012

From the title ” Hepatitis C Medicine Shows 100% Cure Rate”,  you’d think the silver bullet has finally been found and there is no reason to look further. Is this serious competition with Abbott’s recent all oral treatment success? Maybe.  But wait. The first sentence says “a small number of patients.”  At this point, the Gilead trial only involves 25 patients and one had to drop out.  I’ll say that’s small! The Abbot study involved almost 571  patients with a 99% cure rate.

Gilead Sciences 100% Cure Rate

Apparently there was hope earlier that Gilead and Bristol-Myers Squibb would combine their drugs, Sofosbuvir and Declatasvir respectively, after a trial of 44 genotype 2/3 patients and 44 genotype 1 patients showed an almost 100% cure rate. There was a small outcry that these two pharmaceuticals should hash out their differences so the world can be rid of HCV. But again, the original trial showing success was not all that big. By the numbers, I’ll pull for Abbott at this point in the competition. Am I missing something? What do you think?

Gilead Sciences and Bristol-Myers Squibb Won’t Work Together

Abbott Releases Favorable Data on Interferon-free HCV Trial

Wednesday, October 17th, 2012

Keep your eye on this combination Interferon-free treatment as one of the front runners:

“Abbott on Monday announced initial data from a Phase IIb study suggesting that an interferon-free combination regimen of oral drugs resulted in a sustained virologic response (SVR) after 12 weeks in 99 percent of treatment-naïve patients with genotype 1 hepatitis C. In addition, 93 percent of null responders achieved a SVR.”

Abbot 3 Drug Interferon-free HCV Trial

All Oral Regimens for HCV Treatment Promise to be the Silver Bullet

Wednesday, September 26th, 2012

This article, while centering on the stock value of new HCV treatments, gives a good run down on the most promising HCV future treatments.
HCV Drug Competition

Medivir to Begin Phase IIa Interferon Free Hepatitis C Trial of Simeprevir

Wednesday, September 26th, 2012

The race is on to find an effective Interferon Free treatment of HCV. Researchers say it will be possible, but is this the drug of choice?
Phase IIa Interferon Free Combination Hepatitis C Trial of Simeprevir

Medical Device Lowers HCV Viral Load

Friday, August 10th, 2012

Bristol’s Halted Hepatitis C Trial Reinforces Aethlon Medical’s Non-Toxic Therapy
By Paul Archie · Thursday, August 9th, 2012

In the biotechnology world, the sun rises and set around the two key words “safety” and “efficacy.” A serious safety concern last week resulted in Bristol-Myers Squibb (NYSE: BMY) voluntarily halting its ongoing Phase 2 study of BMS-986094, a drug in development as a new indication for hepatitis C as part of the drug maker’s quest for an all-oral regimen for hep C. A patient who had received a 200 milligram dose of the nucleotide polymerase inhibitor, or “nuke,” suffered heart failure; causing Bristol to stop the trial and begin evaluating participants to determine any correlation between the new drug and the heart damage.

To syndicate this article, or for more information, please contact us online or call (406) 862-5400.

In February, Bristol paid $2.5 billion to acquire Inhibitex, a 163-percent premium to the valuation of Inhibitex at that time, primarily to snag its hepatitis C drug candidate (then called INX-189). The halted trial could seriously hamper Bristol in its race with Gilead (NASDAQ: GILD) and Abbott Labs (NYSE: ABT) to bring a new hepatitis C drug to market. It is widely expected that an all-oral drug therapy for the liver disease that affects about 170 million people across the world will generate billions annually in sales. It is the reason that Bristol paid the premium for Inhibitex and Gilead dished-out $11.1 billion last November to acquire Pharmassets and its hep C drug in development.

Investors that recognize the upside potential of new therapies for hepatitis C should be taking a close look at Aethlon Medical (OTCBB: AEMD), the maker of a first-in-class blood filtration device called the Hemopurifier®. Recently released clinical research by Aethlon showed that the two most recent hepatitis C-infected patients to receive its Hemopurifier® therapy in combination with the standard of care peginterferon+ribavirin (PR) drug therapy achieved undetectable viral load at day-7. In lay terms, that means that none of the hepatitis C virus was found in the patients’ bloodstream after seven days of treatment.

As an adjunct, the Aethlon Hemopurifier® selectively targets the rapid clearance of the hepatitis C virus from the entire circulatory system to improve benefit, dose, duration and tolerability of drug therapies. Drugs, like that of Bristol, Gilead or Abbott, carry substantial safety risks because they are “additive” in nature, meaning that they are putting a foreign substance into the body. Aethlon’s Hemopurifier® is “subtractive.” It removes the virus through a proprietary filtering process, which does not carry the same, potentially deadly toxicity risks that can cost major pharma billions to finally realize.
We encourage you to read our previous article for more information on Aethlon’s latest trial results, linked here.

The OTC Investor (http://s.tt/1kpgX)

Highlights from the 47th Annual Meeting of the European Association for the Study of the Liver.

Friday, June 1st, 2012

 

Paul Targett-Adams, Principal Scientist at Medivir AB

 

“4. Summary.

Professor Pawlotsky concluded the meeting with a closing summary talk in which he commented favourably upon the >90% SVR rates we are now seeing but was critical of the very small patient numbers used in many of the studies. Patient cohorts containing as few as 10 ‘ideal’ individuals provide limited opportunity for extrapolation to a real-world setting where HCV-infected patients are often co-infected with HIV or HBV and exhibit varying degrees of liver diseases. He added, “Studies must be powered to be conclusive, percentages (SVR) cannot be interpreted without their 95% confidence intervals, statistical differences must be achieved to support statements of superiority”. Professor Pawlotsky was also critical of the generic statement heard so often at this meeting in relation to clinical evaluation of new therapeutic regimens “….demonstrated high efficacy and a good safety profile”. This is clearly not good enough; safety profiles need to investigated and reported thoroughly, particularly considering the shock news that alisporivir (a host-targeted antiviral specific for cyclophilin A; a cellular factor required for HCV to replicate, currently in Phase III evaluation) has been placed on clinical hold by the FDA following 6 reported cases of acute pancreatitis, including 1 fatality. So to conclude, when can we say ‘goodbye’ to interferon-based regimens? Certainly not quite yet, but it’s becoming increasingly likely that all-oral interferon-free treatments will prevail in the not too distant future. However, the ideal drug combination has yet to be found and treatment duration (and DAA composition) will vary according to patient groups. We are still rather far away from a single once-daily pill that can cure all HCV-infected patients regardless of their particular stratification. Professor Pawlotsky concluded the meeting by stating “large-scale clinical trials are needed to establish reliable efficacy and safety profiles” – I think we can all agree with this particular sentiment.”

Read the entire article here:

http://gastrohep.tv/easl-2012/?goback=%2Egde_3207213_member_120124593

 

Hepatitis C ‘Switch’ Offers Target for New Drug Research

Friday, June 1st, 2012

“Hepatitis C ‘Switch’ Offers Target for New Drug Research

Viral Scientists have discovered a “switch” in the hepatitis C virus which could be used as a target for new kinds of drug treatment. Hepatitis C affects more than 170 million people worldwide, but current combination treatment is only effective against a limited range of this naturally highly variable virus. However, according to new research by the University of Warwick, the newly discovered SL9266 ‘switch’ is very highly conserved and present in all hepatitis C viruses, meaning this offers a good starting point for further research into an across-the-board treatment.

This region represents a vulnerable spot for attacking and clearing the virus from the body as it controls a critical event in the earliest stages of the virus lifecycle. It seems the switch modulates the mutually incompatible translation and replication processes that must occur for the virus to spread inside the body.”

Read more here:

http://viralmatters.blogspot.com/2012/05/sl9266-switch-in-hepatitis-c-

HCV Patients May Be Able to Delay Treatment

Friday, June 1st, 2012

HCV research is rapidly progressing. If you fall in the low risk category and your disease is on hold, you may be able to wait until getting treated. Of course, this is a judgement call. Read more here:

http://viralmatters.blogspot.com/2012/05/ddw-hcv-patients-may-be-able-to-delay