April 28, 2013

April 28, 2013 | By John Carroll

What if you had a great combination of rival drugs that worked in 100% of patients, but one of the companies involved refused to participate in the trials needed for an approval? If you're Gilead ($GILD), the answer is to continue to ignore compelling data, shun the competitor drug and stay focused on an in-house combo that could deliver a big segment of the market. But some patients and doctors appear willing to consider taking matters into their own hands.

Over the weekend investigators went over the numbers for sofosbuvir and daclatasvir, which demonstrated that after 12 weeks the combo cleared 100% of the virus among 40 patients who had already failed the two leading therapies, Incivek and Victrelis. That's the toughest group of patients to target. And there was solid proof that the combination worked among patients in the genotype 3 group, a sizeable minority of the market in key regions of the world.

Gilead's sofosbuvir is the $11 billion jewel the biotech acquired with the Pharmasset buyout. But after finding that it worked to perfection in combination with competitor Bristol-Myers' ($BMY) great hep C hope, daclatsvir, Gilead determined its best market opportunity lay with its own in-house combination with ledipasvir (GS-5885). Investigators like Graham Cooke at Imperial College say that sofosbuvir/ledipasvir looks like a clear winner in the large genotype 1 population, but G3 patients may be missing out on sofosbuvir/daclatasvir.

"We probably have a better option for G3 that we could be using if the companies were cooperating," Cooke told Bloomberg. "Daclatasvir and sofosbuvir looks much better but Gilead very clearly wants to develop in-house."

Both daclatasvir, now combined in a number of clinical studies with outside drugs, and sofosbuvir appear headed for approvals. That opens the door to an off-label combo. Provided patients could afford it, payers would cover it and doctors can be satisfied that it's safe without a pivotal Phase III study.

"Lots of investigators around Europe and the U.S. are itching for the opportunity to put together what they believe to be the optimum combination for our patients," Mark Thursz, the secretary-general of the European Liver Society, told Bloomberg. "The only barrier to that is what is the combination cost going to be because I suspect there will be package deals to be had."

- here's the report from Bloomberg

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Also See:

  1. Gilead-Bristol Hepatitis C Drug Combo Cures All in Study (April 28, 2013)
  2. Gilead-Bristol Hepatitis C Combo Cures 100% of Patients in Study (April 27, 2013)

By News Staff | April 28th 2013 03:00

A drug developed by Gilead Sciences and tested in an animal model at the Texas Biomedical Research Institute in San Antonio suppresses hepatitis B virus infection by stimulating the immune system and inducing loss of infected cells.

Hepatitis B virus (HBV) damages the liver, leading to cirrhosis and liver cancer. Liver cancer is the fifth most common cancer worldwide and the third most common cause of cancer death. According to the United States Centers for Disease Control and Prevention (CDC), up to 1.4 million Americans are chronically infected with HBV. The World Health Organization estimates that two billion people have been infected with the hepatitis B virus, resulting in more than 240 million people with chronic infections and 620,000 deaths every year.

In the study, researchers found that the immune modulator GS-9620, which targets a receptor on immune cells, reduced both the virus levels and the number of infected liver cells in chimpanzees chronically infected with hepatitis B virus. Chimpanzees are the only other species that can be infected by HBV so the results from this study were critical in moving the drug forward to human clinical trials.

Gilead researchers had previously demonstrated that the same therapy could induce a cure of hepatitis infection in woodchucks that were chronically infected with a virus similar to human HBV.

"This is an important proof-of-concept study demonstrating that the therapy stimulates the immune system to suppress the virus and eliminate infected liver cells," said co-author Robert E. Lanford, Ph.D., of Texas Biomed. "One of the key observations was that the therapy continued to suppress virus levels for months after therapy was stopped.

The current therapy for HBV infection targets the virus and works very well at suppressing viral replication and delaying progression of liver disease, but it is a lifelong therapy that does not provide a cure.

"This GS-9620 therapy represents the first conceptually new treatment for HBV in more than a decade, and combining it with the existing antiviral therapy could be transformative in dealing with this disease," stated Lanford.

The Gilead drug binds a receptor called Toll-Like Receptor 7 that is present in immune cells. The receptor normally recognizes invading viruses and triggers the immune system to suppress viral replication by the innate immune response and kill infected cells by the adaptive immune response, thus orchestrating both arms of the immune system.

Published in
Gastroenterology (dx.doi.org/10.1053/j.gastro.2013.02.003)

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Presented at EASL

By Shazia Qureshi

AMSTERDAM, the Netherlands -- April 27, 2013 -- Adding azathioprine to tacrolimus led to a slower onset of severe fibrosis in patients who received a liver transplant because of hepatitis C virus (HCV)-related cirrhosis, according to a study presented at the 48th Annual Meeting of the European Association for the Study of the Liver (EASL).

In addition, the combination therapy seemed to lower the chance of portal hypertension.

The findings of the 8-year study were presented on April 25 by Pinelopi Manousou, MD, Royal Free Sheila Sherlock Liver Centre, at the University College London, London, United Kingdom.

“Optimal immunosuppression treatment for these patients is still under debate” she said. “Immunosuppression worsens the severity of HCV recurrence.”

A total of 103 adult patients were randomised to receive either tacrolimus monotherapy (n = 54) or triple therapy (n = 49), which consisted of tacrolimus (0.1 mg/kg in divided doses), azathioprine (1 mg/kg), and prednisolone (20 mg/day, then tapered off to zero by 3 to 6 months).

Time to stage 4 fibrosis (on the Ishak scale of 0 = no fibrosis to 6 = cirrhosis) was one of the primary endpoints.

Over a median of 96 months of follow-up, stage 4 fibrosis was reached by 19 patients on monotherapy and by 11 patients taking triple therapy, with the triple therapy group showing slower fibrosis progression (median of 49 months vs 32 months with monotherapy; P = .005).

The researchers also measured fibrosis using the collagen proportionate area (CPA). Among those patients in whom it was measured, CPA was found to be ≥6% in 20 of 39 patients in the monotherapy group and in 13 of 39 patients in the triple therapy group. When the cut-off used was ≥7.2%, this was seen in 21 of 39 patients in the monotherapy group and in 14 of 39 patients in the triple therapy arm.

Portal hypertension was defined as hepatic venous pressure gradient (HVPG) ≥10 mmHg. Among those in whom HVPG was measured, it was found to be ≥10 mmHg in 11 of 33 patients in the monotherapy group and in 4 of 31 patients in the triple therapy group.

“The triple therapy arm has the lowest fibrosis progression rate published in the literature to date,” said Dr. Manousou. “This regimen could be considered as a first choice for HCV [liver] transplant patients, until such time as other evidence proves otherwise.”

[Presentation title: Long Term - 8 Year Follow-Up of a Randomized Trial of Tacrolimus Monotherapy versus Triple Therapy After Liver Transplantation for HCV Cirrhosis. Abstract 25]

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Presented at EASL

By Shazia Qureshi

AMSTERDAM, the Netherlands -- April 27, 2013 -- Sustained virological response 4 weeks after the end of treatment (SVR-4) was reached by as many as 65% liver transplant recipients with hepatitis C virus (HCV) genotype 1 who were receiving antiviral triple therapy with pegylated interferon, ribavirin, and a protease inhibitor (PI).

“However, these results must be balanced with high rates of adverse events observed,” said Elizabeth Verna, MD, Columbia University College of Physicians and Surgeons, New York, New York, on April 25 at the 48th Annual Meeting of the European Association for the Study of the Liver (EASL).

The study cohort included 112 liver transplant recipients with HCV who were receiving antiviral triple therapy with pegylated interferon, ribavirin, and a PI (telaprevir or boceprevir).

The median time from liver transplantation to start of triple therapy was 3.7 years. Prior to triple therapy, 96% of patients had undergone a lead-in period with only pegylated interferon plus ribavirin, mainly because the PIs used in the study only recently became available in 2011. Immunosuppression treatment was also administered and included cyclosporine, tacrolimus, steroids, and mycophenolate mofetil (MMF).

From the data collected so far, 64% of patients have shown an extended rapid virological response (eRVR), defined as undetectable HCV RNA levels at weeks 4 and 12.

So far, 48 patients have had the opportunity to reach SVR-4 (48 weeks of treatment plus 4 weeks of follow-up). Among them, 63% have shown eRVR and 65% have shown SVR-4. In addition, SVR-4 rates were 93% among those with eRVR -- which may be an important predictor of response, according to Dr. Verna.

Six percent of patients died (4% liver-related, 2% non-liver-related). Hospitalisation due to serious adverse events occurred in 21% of patients, with the rate being higher among the 30 patients with advanced disease (38%) than among the 82 patients without advanced disease (16%; P = .02).

Renal failure -- defined as an increase in serum creatinine level of >0.5 mg/dl -- was reported in 34% of the whole cohort, again with a difference between patients with and without advanced disease (47% vs 30%).

“The results are preliminary, and improving tolerability and identifying predictors of SVR is critical to optimising the risks and benefits of post-liver transplant triple [antiviral] therapy,” said Dr. Verna.

[Presentation title: A Multicenter Study of Protease Inhibitor-Triple Therapy in HCV-Infected Liver Transplant Recipients: Report From the CRUSH-C Group. Abstract 23]

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Filed under Health, Research on Friday, April 26, 2013.

GAINESVILLE, Fla. — Two antiviral drugs used to treat hepatitis C appear to work as well in the real world as they did during clinical trials, an international research consortium has observed. The consortium also released data that may help inform how doctors and patients manage treatment-related adverse events.

The international effort, known as HCV-TARGET, follows how newly approved therapies for hepatitis C are used and managed in routine practice. It is led jointly by the University of Florida and the University of North Carolina at Chapel Hill.

The ongoing research suggests that the safety and efficacy of the antiviral drugs telaprevir and boceprevir are similar for North American patients taking the treatments in real-world settings to what was observed in clinical trials.

The evaluation of data available from November 2011 through April 2013, presented at the 48th Annual Meeting of the European Association for the Study of the Liver in Amsterdam, found that anemia was the most relevant adverse event affecting clinical care. Approximately two-thirds of anemic patients were managed with drug dose reductions, which minimized the need for expensive growth factors and blood transfusions. The analysis also reveals that patients with cirrhosis were at increased risk for treatment-related complications, including severe anemia and significant deterioration of the liver, which often resulted in stopping therapy early.

“This is a long-term study, and we plan to release similar interim analyses each spring and fall to provide clinicians with up-to-date knowledge that can inform how we manage therapy for patients with hepatitis C,” said Dr. David R. Nelson, co-principal investigator, director of the UF Clinical and Translational Science Institute and professor of medicine at UF, which serves as the clinical coordinating center for HCV-TARGET.

One of the consortium’s priorities for future analyses will be to investigate indicators that may predict adverse outcomes in cirrhotic patients and guide safer use of these drug regimens.

Hepatitis C is a viral liver disease transmitted through contact with infected blood. Chronic hepatitis C can lead to serious liver problems including liver damage, cirrhosis, liver failure or liver cancer. Because a person with chronic hepatitis C can live symptom-free for many years, many people do not know they are infected.

Globally, the World Health Organization estimates about 150 million individuals are chronically infected with hepatitis C, and more than 350,000 people die each year from hepatitis C-related liver diseases. In the U.S., the Centers for Disease Control and Prevention estimates 3.2 million people are chronically infected with hepatitis
C, although a 2011 review article in Liver International suggests the estimate is likely higher — at least 5.2 million people — if U.S. populations not surveyed by the CDC are included, such as the homeless and incarcerated.

HCV-TARGET was created to inform the ongoing transformation of hepatitis C treatment and research. The HCV-TARGET model is rooted in the infrastructure and collaborative network developed through the National Institutes of Health’s Clinical and Translational Science Award (CTSA) program, which is led by the National Center for Advancing Translational Sciences. In addition to UNC and UF, HCV-TARGET includes 23 other CTSA-supported institutions among its 103 academic and community sites in 31 states, Puerto Rico, Canada and Europe. HCV-TARGET also partners with multiple industry sponsors, regulatory agencies and the patient advocacy community.

In 2011, HCV-TARGET established a nationwide registry to observe patients in the United States undergoing hepatitis C treatment over time and to coordinate real-world monitoring on a national scale for new therapies as they enter the market. For patients who agree to be in the study, the project is capturing demographic, clinical, adverse event and virological data. To date approximately 1,900 patients have agreed to participate, including patients with cirrhosis and other populations underrepresented in clinical trials.

“The data coming out of the HCV-TARGET consortium will help inform physicians and patients as they weigh important decisions regarding therapy, decisions that can greatly impact quality of life,” said Dr. Donald M. Jensen, a professor of medicine at the University of Chicago and a member of the HCV-TARGET Steering Committee.

The network’s initial study has followed a broad population of adult patients in North America treated with telaprevir or boceprevir, which were newly approved by the U.S. Food and Drug Administration when HCV-TARGET launched. In 2013, HCV-TARGET is expanding its study to include European sites and patients treated with any direct-acting antiviral agent approved by the FDA.

“We plan to track up to 5,000 patients internationally over five years to continue to assess the benefits and risks of new treatments in real-world settings,” said Dr. Michael W. Fried, co-principal investigator and professor of medicine at UNC, which serves as the HCV-TARGET data coordinating center. “HCV-TARGET serves as a model for cross-cutting collaborative studies that can rapidly advance knowledge in an important illness of public health concern.”

HCV-TARGET (www.hcvtarget.org) receives ongoing industry support from Merck, Genentech, Kadmon, and Vertex. Dr. Fried receives research grant support from and serves as ad hoc consultant to Genentech, Vertex, Merck, Gilead, Bristol Myers Squibb and Abbott. Dr. Nelson receives grant support from Genentech, Kadmon, Merck, Vertex Pharmaceuticals, Gilead, Boehringer Ingelheim and Abbott/Abbvie; and payment for the development of educational presentations from Clinical Care Options, Rush University Medical Center, Practice Point Communications and Chronic Liver Disease Foundation.

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Media Contact
Claire Baralt, cbaralt@ufl.edu

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Gilead-Bristol Hepatitis C Drug Combo Cures All in Study

By Simeon Bennett - Apr 28, 2013 12:14 PM ET

A hepatitis C drug combination fromGilead Sciences Inc. (GILD) and Bristol-Myers Squibb Co. (BMY) cured all patients in a trial, demonstrating the success of a cocktail that may never be approved.

In a study among 41 patients of Gilead’s sofosbuvir with Bristol’s daclatasvir, with or without the generic antiviral ribavirin, 40 were virus-free 12 weeks after six months of treatment, according to results presented yesterday in Amsterdam. The other patient didn’t turn up to the last appointment and was later found to be virus-clear. All the patients had failed prior treatment with either Vertex Pharmaceuticals Inc. (VRTX)’s Incivek or Merck & Co. (MRK)’s Victrelis

The lack of a late-stage study, and the expense of the pills, will probably put the Gilead-Bristol combination out of reach for doctors and patients, said Geoffrey Dusheiko, a professor of medicine at the Royal Free Hospital in London.

“It’s a conundrum for us,” Dusheiko said in an interview after the results were presented at the European Association For the Study of the Liver’s conference. “It looks a very promising regimen, it really does. But I’m really not sure it’ll see the light of day.”

Still, doctors may be tempted to prescribe the Gilead-Bristol combo “off-label” once both drugs are approved, saidMark Thursz, secretary-general of the European liver association.

“Lots of investigators around Europe and the U.S. are itching for the opportunity to put together what they believe to be the optimum combination for our patients,” Thursz said.“The only barrier to that is what is the combination cost going to be because I suspect there will be package deals to be had.”

Previous Success

The combination had previously demonstrated success in patients who hadn’t been treated before. Those who have failed Incivek or Victrelis are “perhaps the most difficult-to-treat population” and have no current options, said Mark Sulkowski, a doctor at Johns Hopkins University in Baltimore who presented the results.

Bristol-Myers, based in New York, was working on the combination with Pharmasset Inc., which developed sofosbuvir, when Gilead bought the company for $10.8 billion in 2011. Gilead subsequently focused on developing sofosbuvir in combination with its own drug, ledipasvir. That combination cured 100 percent of patients in a mid-stage patient study, and the company is testing it in two late-stage studies.

Combo Trials?

Gilead and Bristol have planned no further trials of the combo because Foster City, California-based Gilead is focusing on a cocktail that contains only its own drugs. “We believe that we have been able to advance the development of SOF (sofosbuvir)/ledipasvir much more quickly than would have been possible with any inter-company collaboration,” Gilead’s chief scientific officer Norbert Bischofberger said in an e-mail.

Bristol is “committed to driving advances in hepatitis C research both through internal development and external collaborations to study the best treatments” and is working with Johnson & Johnson (JNJ)’s Janssen unit to study daclatasvir with simeprevir, it said in an e-mail.

Still, while ledipasvir may be effective against patients with hepatitis C genotype 1, the most common form worldwide, it may not work for those with genotype 3, which accounts for about 25 percent of cases in Europe and 45 percent in the U.K., saidGraham Cooke, a clinician at Imperial College London. Daclatasvir and sofosbuvir are both active in that group, he said.

“We probably have a better option for G3 that we could be using if the companies were cooperating,” Cooke said in an interview. “Daclatasvir and sofosbuvir looks much better but Gilead very clearly want to develop in-house.”

Off-Label Combo?

Prescribing the two drugs as an off-label combination may be too expensive because they’ll probably have high prices as individual therapies whereas Gilead’s cocktail may be cheaper, he said.

Off-label use may also be dangerous, said Jean-Michel Pawlotsky, a professor of medicine at the University of Paris-Est.

“We don’t have enough safety data,” Pawlotsky said in an interview. “If a doctor does that and there’s a major accident, the doctor is liable. It’s dangerous but I know that people will do it.”

Bristol-Myers agreed last week to study daclatasvir in combination with Merck’s MK-5172. This month it also agreed totest the drug together with Cambridge, Massachusetts-based Vertex’s VX-135.

To contact the reporter on this story: Simeon Bennett in Geneva at sbennett9@bloomberg.net

To contact the editor responsible for this story: Phil Serafino at pserafino@bloomberg.net

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Also See: Gilead-Bristol Hepatitis C Combo Cures 100% of Patients in Study (April 27, 2013)

Liver transplants: Driven by desperation

Ethar Shalaby / April 28, 2013

In Egypt, the chronic liver disease Hepatitis C is a major concern in medical circles. Specialists are recording an increasing rate of infection in the country, and liver transplants are sometimes the only solution. However, it can be extremely difficult to find liver donors in Egypt.

4-1-1-liver-transplant

Liver transplant operations last from eight to 12 hours
(AFP Photo / Noel Celis)

As Egypt records one of the highest infection rates of Hepatitis C worldwide, hundreds of thousands of patients, especially those who have reached end stage liver disease, struggle due to liver failure. Only a lucky few manage to recoup their health and independence through a liver transplant. It is not easy. A typical Hepatitis C patient undertakes a long journey before finally locating an eligible donor who consents to donate more than half of his or her healthy liver.

Scientifically, end-stage Hepatitis C entails the destruction of the liver, which is severely affected by the Hepatitis C virus. The virus is stealthy, and once contracted, can silently damage the liver enzymes for over twenty years without the patient becoming aware of the problem. Eventually, the disease may progress to cause fibrosis of the liver. In some cases, if the liver is less severely damaged, a drug called interferon may be able to halt the disease by suppressing the active virus. Interferon is a long-term treatment and does not usually lead to the total eradication of the virus. Therefore, liver transplants, entailing the replacement of the diseased liver with all or part of a healthy one, are the most effective solution for Hepatitis C sufferers.

According to ‘Hepatitis C: The cure’, an article published in March 2013 by the Financial Times magazine, the virus has always been elusive and difficult to treat. “No one knows how the virus got started: maybe in dogs, or bats. Different variations, known as genotypes, exist in different parts of the world. It has certainly existed for thousands of years, but because the virus travels in the blood, for centuries it never moved very far,” reads the article. For more than 20 years, the virus was known merely to be a type of hepatitis, denoting an inflammation of the liver, and was described as “non-A, non-B hepatitis”. Scientists and liver specialists are currently debating the effects and use of Sofosbuvir, a newly-developed drug that scientists hope will be a breakthrough treatment for Hepatitis C. A week ago, news was released that Sofosbuvir had improved the cure rate of two subtypes of Hepatitis C, according to the UPI.com health journal.

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A donor supplies the Hepatitis C patient with about 60 per cent of his healthy liver
(AFP Photo)

Samaah’s story

In many poor neighbourhoods across Cairo, millions of Egypt’s citizens struggle to survive. Illiterate, desperate, and hungry, many choose to undergo liver transplants as donors in return for large sums of money. Samaah is one of those.

“My husband is a drug addict. I don’t depend on him to provide for our kids or me financially. But, I needed the money urgently to help my daughter get married,” says Samaah, who donated 60 per cent of her liver to a Hepatitis C sufferer for EGP 50,000. Lying in her bed after undergoing almost 10 consecutive hours of invasive surgery, the 37-year-old cleaning lady at a school says she is totally convinced that her decision to donate a large section of her liver to another patient was a good one. “I am happy I did that, and I knew it was very risky and could lead me to serious health problems,” she says. Only recently did it cross Samaah’s mind that she could quickly earn EGP 50,000 in return for 60 per cent of her liver. Samaah’s story started when she heard of a Hepatitis C patient asking around for an eligible donor. At a private school in the Cairo neighbourhood of Haddaiyeq Al-Qubba, the donor chatted with a common friend about her decision to give away part of her healthy liver to save another Egyptian.

“I was sitting with one of my colleagues at work when she told me that there was a teacher who was suffering from end-stage liver disease and was offering a lot of money to an eligible liver donor,” she explains. Living with her two sons and soon to be married daughter, Samaah states that her dire need for money was the main factor behind agreeing to undergo the liver transplant surgery. “I honestly knew it was dangerous for me, but I decided to undergo the operation and I only told my husband and sister about it. None of my kids know that I have donated a big part of my liver,” she says.

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Donors usually get out of the surgery five hours before the patient does
(AFP Photo)

The donation

Dr. Wahid Doss, Dean of the National Liver Institute, explains that before proceeding with any liver transplant surgery doctors usually sit with the donor and explain to him/her all the possible side effects that could result from the operation. These can include pneumonia, blood clots on the lungs, temporary liver failure, and even death. “The donor listens carefully to all the side effects and has to sign many consent forms stating that he/she fully understands and agrees to the procedure,” says Doss. He adds that although Samaah was firmly convinced to undergo the procedure from the very beginning, many donors change their minds after reflecting on the possible post-surgery side effects of the transplant. “For some people, it is all about the money,” Doss explains.

Samaah, who used to weigh 94 kilos, had to lose more than 20 kilos in three months in order to be able to donate part of her healthy liver. “Three months before the surgery, I had follow-up meetings with the doctors and I underwent various blood tests, liver enzymes tests and many other scans. I was told that I had to lose a lot of weight before the liver transplant,” she says.

Explaining the exact procedures of a liver transplant, Doss states that a Hepatitis C patient seeking a transplant is usually faced with two problems. The first is to be able to find an eligible donor; the second is to be financially able to afford the liver transplant surgery. The cost of typical liver transplant surgeries in Egypt ranges from EGP 200,000 to EGP 400,000 including the hospital expenses. The first step taken after a patient finds a donor is to present all his documents and test results to an ethical committee, usually found at any hospital, to study the case. “Liver transplants have a humanitarian aspect. If the donor is not a relative, the committee needs to assess whether or not he/she is supplying the biggest part of his/her liver without any pressure from anyone,” Doss says, elaborating that in some cases “coercion” from families and friends can take place. The committee then transfers the file to the High Committee of Organ Transplant, which belongs to the Ministry of Health, to give the case final approval. The High Committee of Organ Transplant was established in Egypt due to Law 5, which was passed in 2010, and exists to regulate all organ transplants across the country.

According to Doss, Egyptian law rules that a donor may be any of the patient’s relatives who is between the ages of 20 and 40 and is free of any diseases. He points out that only about 22 hospitals in Egypt perform liver transplants, including educational hospital universities, military hospitals and a small number of private hospitals. In 2012, the country finally issued a law that sets the rules for general organ transplant.

Meeting the legal conditions to become an eligible donor is not easy. The husband of the Hepatitis C sufferer to whom Samaah donated part of her liver speaks about how difficult it was to find an eligible donor. “After finding out that my wife was suffering from end-stage liver disease, we kept asking around everywhere for an eligible donor. Nobody was suitable in her case. Many donors accept a deposit of EGP 5,000 and then flee away,” he says. Doss says he hears of hundreds of cases of intended donors who take the money but simply disappear as little as one hour before the surgery takes place. “There is a lot of trickery and many con-artists in the liver transplant process,” the patient’s husband, who preferred to remain anonymous, says. Before Samaah came on the scene, he explained, the family struggled to find an appropriate donor to save his wife’s life.

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Volume rendering image created with computed tomography which can be used to evaluate the volume of the liver of a potential donor
(Photo from Taichung Veterans General Hospital)

Role of the broker

A broker, who mediates between donors and patients, says he usually receives about 10 per cent of the total cost of the surgery. “I help Hepatitis C patients find a relevant donor. If we agree on the price of the donation I begin to search for an eligible donor,” he says. The broker, who refuses to give his name, explains that there are many others who earn money from the liver transplant business. “I work closely with doctors who treat Hepatitis C and I have been working in this business for about seven years,” he says. When the broker brings in a potential donor, he receives around EGP 10,000 and the donor takes about EGP 5,000 until he or she passes all the requested blood tests. “If the tests prove he or she can medically proceed with the surgery, I take another EGP 5,000 after the completion of the surgery,” the broker says.

But the patient’s husband says that they tried to approach several liver brokers. Two brokers took deposits for their services, promising to find the couple an eligible donor, but then disappeared. “Some brokers are thieves. It was only thanks to good luck that we managed to get in contact with Samaah,” he says.

Doss elaborates that the donor should be a close relative of the patient and has to have the same blood group as the patient, a liver which is large and healthy enough to donate a piece, and should be free from any diseases with good results in all liver function tests. If the donor is not a relative, doctors need to apply the same criteria if they are considering a foreign donor and also make sure he or she understands the risks he or she is putting him or herself through. The transplant operation usually lasts from 8 to 12 consecutive hours.

“I knew it was going to last for many hours. I stayed in surgery for about 8 hours and then I got out. The patient receiving part of my liver stayed in surgery for another five hours,” Samaah says.

Rise in surgeries

Since 2001, around 2,000 liver transplant surgeries have been conducted for Hepatitis C patients. Gamal Heshmat, a professor of liver diseases at Qasr El-Einy hospital, says that during 2012 alone Egyptian doctors performed 300 to 400 liver transplant operations. He adds that there are about 150,000 Hepatitis C sufferers in Egypt, and about 15,000 of them are experiencing end-stage liver failure and require liver transplants immediately.

“The problem lies not only in the high number of the patients already diagnosed with Hepatitis C, but also in the growing number of people who are infected every year by the same virus,” Heshmat says. He explains that every year about 15,000 people discover that they are carrying the virus, which is transferred through the blood in procedures like blood transfusions or the use of unsterilised medical equipment. “Most of the infections occur inside medical institutions, in hospitals, clinics or other medical centres in Egypt,” the liver specialist says.

In October 2012, the National Committee for the Control of Viral Hepatitis established the country’s first Hepatitis C patient registry. This has helped many patients to connect with others who have been treated with Interferon to combat the virus. This registry has helped to assess the extent of many other related issues to the virus, analyse new data and recognise the most common methods of infection.

“I will get out of the hospital tomorrow morning. After the surgery was finished, I received the rest of the money that we agreed on before the surgery. I actually think it was great that I managed to save a person’s life and at the same time managed to earn a lot of money very quickly,” Samaah says, adding that she will start preparing for her daughter’s wedding as soon as she recuperates.

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Triple Therapy Can Help in Advanced Hep C

By Michael Smith, North American Correspondent, MedPage Today

Published: April 28, 2013

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco

AMSTERDAM -- About 40% of people with advanced hepatitis C (HCV) can benefit from triple therapy even if they have cirrhosis and previous treatment failures, a researcher said here.

An interim analysis of a large cohort of patients in France found that benefit following treatment with one of the recently approved HCV protease inhibitors, telaprevir (Incivek) or boceprevir (Victrelis), when each was combined with pegylated interferon and ribavirin, according to Helene Fontaine, MD, of Cochin Hospital AP-HP in Paris.

But the benefit was counterbalanced by a high risk of serious adverse events, Fontaine reported at the meeting of the European Association for the Study of the Liver (EASL).

Triple therapy has been shown to improve outcomes for most HCV patients, commented Laurent Castera, MD, PhD, of Centre Hospitalier Universitaire in Bordeaux, France, who was not involved in the study but who moderated an EASL press conference.

But it's not well understood how very sick patients will respond to treatment because they have been largely left out of clinical trials, he said, and those who have been treated have generally had poor outcomes.

"The paradox is that for the patients who most need treatment – patients with cirrhosis and treatment-experienced patients – results have been pretty disappointing," he said.

The current study, which is from the French early access program, may go some way toward clarifying what can be expected from triple therapy in very sick patients, he said.

The CUPIC study (for Compassionate Use of Protease Inhibitors in viral C Cirrhosis) now includes some 674 cirrhotic or treatment-experienced patients treated at 56 sites from Feb. 15, 2011 to April 12, 2013.

The primary endpoint is the rate of undetectable HCV RNA 24 weeks after the end of the therapy (SVR24). But since many patients have not reached that mark, Fontaine reported SVR12 data for 485 patients, or 72% of the cohort.

In that subgroup, 295 patients were treated with telaprevir (Incivek) and 190 with boceprevir (Victrelis), both combined with pegylated interferon and ribavirin, Fontaine said. The study is observational, with no randomization, and the treatment choice is left to the patient and his or her doctor, she noted.

Response rates – defined as undetectable HCV viremia -- in the telaprevir patients reached a high of 81% at week 12 of treatment, but then tailed off to 56% at week 48, the end of treatment, Fontaine said.

Twelve weeks later, 40% of patients still had undetectable HCV RNA and had achieved an SVR12.

The pattern among the boceprevir patients was "not different," Fontaine said – the response rates peaked during therapy, fell to 57% at the end of treatment, and 41% of patients achieved SVR12.

In either case, patients who had previously responded to treatment pegylated interferon and ribavirin but then relapsed did better, with SVR12 rates of 53% for telaprevir and 51% for boceprevir, than those who had never responded or had a partial response.

In addition, patients with the HCV 1a genotype did worse than those with genotype 1b, regardless of the protease inhibitor.

A multivariate analysis found that patients who relapsed had an odds ratio for SVR12 of 2.03 (95% CI 1.38 to 3.0) compared with null or partial responders (P=0.0003).

The analysis also showed that genotype 1b patients had an OR for SVR12 of 1.92 (95% CI 1.3 to 2.84) compared with genotype 1a (P=0.0011).

On the other hand, Fontaine said, rates of serious adverse events were high in both groups.

Among telaprevir patients, there were 535 serious adverse events among 160 patients while 63 patients stopped treatment because of serious adverse events. There were seven deaths.

The researchers noted that 9.1% of patients had severe infections and 12.9% had severe anemia. Anemia of 8 g/dL or blood transfusion was reported in 17.8% of cases.

Among boceprevir patients, the pattern was similar: There were 321 serious adverse events among 97 patients and 27 patients stopped treatment because of serious adverse events. There were three deaths.

Also, 4.2% of patients had severe infections and 10% had severe anemia. Anemia of less than 8 g/dL or blood transfusion was reported in 8.7% of cases.

She concluded that while some patients – especially those who had relapsed after previous therapy and those with genotype 1b disease – can do well on triple therapy, the benefit "should be balanced" with the risks of serious adverse events.

The study was supported by ANRS. Fontaine reported financial links with Jannsen, BMS, MSD, Roche, and Gilead.

Castera reported financial links with BMS, Merck, Gilead, and Echosens.

Primary source: European Association for the Study of the Liver
Source reference:
Fontaine H, et al. "SVR12 Rates and Safety of Triple Therapy Including Telaprevir or Boceprevir in 221 Cirrhotic Non-Responders Treated in the Frent Early Access Program (ANRS CO20-CUPIC)." EASL 20113;abstract 60.

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New Drug Holds Promise in Hepatitis C

By Michael Smith, North American Correspondent, MedPage Today

Published: April 28, 2013

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco

AMSTERDAM -- An investigational protease inhibitor for hepatitis C (HCV) achieved high response rates in treatment-naive patients when given in what one expert called an "old-fashioned" regimen.

The drug (MK-5172) rendered the virus undetectable 24 weeks after the end of therapy in almost 90% of patients with the difficult-to-treat HCV genotype 1, according to Michael Manns, MD, of Hannover Medical School in Hannover, Germany.

In contrast, treatment with an approved protease inhibitor, boceprevir (Victrelis), led to an SVR24 in just 54%, Manns reported at the meeting of the European Association for the Study of the Liver (EASL).

But both drugs were combined with pegylated interferon and ribavirin, medications that are widely regarded as likely to fade from practice as a range of investigational direct-acting agents reaches the clinic.

The direct-acting agents, such as boceprevir and MK-5172, attack elements of the virus, in contrast to interferon and ribavirin, which respectively boost the immune system and target general viral replication.

Both have a range of unpleasant side effects and interferon in particular is seen as both difficult to tolerate and dangerous to use.

MK-5172 "is a very good drug," commented Alessio Aghemo, MD, of the University of Milan in Italy, who was not involved with the study but who moderated the EASL session at which it was presented.

But he told MedPage Today that clinicians and researchers are withholding judgment until it is tested without interferon and perhaps without ribavirin.

"The SVR rates are high with (interferon and ribavirin) but it's an old-fashioned regimen," he said. "It needs to go into an interferon-free regimen."

The study, Manns reported, included 332 treatment-naïve patients with genotype 1 virus and without cirrhosis. They were randomly assigned to one of four doses (100, 200, 400, or 800 mg) of MK-5172 or to boceprevir as a control. All patients also received pegylated interferon, and ribavirin for durations that varied according to early treatment response.

Manns presented data on the proportion of patients in each arm who reached SVR24 or who had undetectable virus at their last visit if that occurred before they completed 24 weeks after the end of therapy.

When the data were compiled in March, 311 patients had either reached the 24-week mark or had dropped out of the study before then, but all patients had completed treatment.

Analysis showed that the SVR24 rates in the MK-5172 arms ranged from 86% to 92%, compared with 54% in the boceprevir arm.

When the researcher added those who had not reached the 24-week mark, but who had undetectable virus at their last study visit, the rates ranged from 92% to 99% for MK-5172 and rose to 67% in the boceprevir arm.

Interestingly, there was little variation when the researchers stratified patients by polymorphisms of the IL28B gene, which predicts response to interferon, although the favorable CC allele tended to yield slightly better response rates numerically.

Manns noted that some patients getting higher doses of MK-5172 (400 and 800 mg ) were "down-dosed" to 100 mg daily, which will be the dose used in future studies.

There were no deaths on the study and the rates of serious adverse events were similar – 9% in the combined MK-5172 arms and 8% in the boceprevir arm, Manns said. Adverse events included gastrointestinal problems, rash, and anemia.

Only 7% of patients stopped therapy owing to adverse events in the combined MK-5172 arms compared with 14% in the boceprevir arm.

A total of 26 patients had bilirubin elevations, possibly because MK-5172 inhibitors some transporter molecules and enzymes, he said. The elevations mostly occurred early and were not associated with decreases in hemoglobin.

In general, the drug was well tolerated but the investigators noted dose-related elevations in liver enzymes, he said.

The study was supported by Merck. Manns reported financial links with the company, as well as with Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Novartis, Roche, Idenix, and Valeant.

Aghemo reported financial links with Roche, Gilead, Jannsen, and Merck.

Primary source: EASL 2013
Source reference:
Manns M, et al. "High Sustained Viral Response at 12- and 24-Week Follow-Up of MK-5172 with Pegylated Interferon Alfa-2B and Ribavirin (PR) in HCV Genotype Treatment-Naive Non-Cirrhotic Patients" EASL 2013;abstract 66.

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Shunt Correction Eases Hepatic Encephalopathy

By John Gever, Deputy Managing Editor, MedPage Today

Published: April 28, 2013

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco

AMSTERDAM -- Elimination of spontaneous liver shunts, or reducing the size of surgically placed shunts, is an effective treatment for hepatic encephalopathy in cirrhotic patients, researchers said here.

A retrospective review of 37 European patients undergoing embolization of spontaneous liver shunts, all of whom had encephalopathy prior to the procedure, found that 59% were free of the condition during the first 100 days of follow-up, said Wim Laleman, MD, of University Hospitals Leuven, Belgium.

A few patients had recurrent encephalopathy later on, but the overall clinical success rate was 49%, Laleman told attendees at the European Association for the Study of the Liver's (EASL) annual meeting.

In a separate presentation at EASL, a colleague of Laleman's in Leuven, Frederik Nevens, MD, reported that patients with hepatic encephalopathy after undergoing transjugular intrahepatic portosystemic shunt (TIPS) for preventing variceal bleeding benefited from a shunt reduction procedure.

Among 55 patients with either persistent encephalopathy or a syndrome known as post-TIPS liver failure, a percutaneous procedure to implant a new, smaller stent to reduce the shunt area led to marked clinical improvements, Nevens said.

Hepatic encephalopathy was reduced or eliminated in 25 of 34 patients for whom that was the most prominent post-TIPS problem. In 21 patients also afflicted with liver failure following TIPS, the condition lifted in nine after shunt reduction.

Both researchers emphasized that the results needed to be replicated in larger samples before these procedures could become standards 0f care.

Hepatic encephalopathy is a frequent complication of liver cirrhosis because the organ loses its ability to remove brain-poisoning toxins from the circulation. The problem can be exacerbated when blood flow to or within the liver is compromised by vascular shunts.

Such shunts may occur spontaneously with liver disease, or they may be placed deliberately in an effort to control variceal bleeding.

Shunt Reduction after TIPS

Nevens said that, in the vast majority of cases, TIPS is helpful to liver cirrhosis patients. The 55 patients undergoing the shunt reduction procedure were the treatment failures in a group of 407 TIPS patients.

The shunt reduction was carried out with what Nevens called the "parallel technique," in which a balloon-expandable stent is placed within the existing shunt. He said a femoral approach has been preferred but that a jugular approach was used in some cases. The target reduction in surface area was 36%.

Although responses to the reduction procedure were generally encouraging, particularly in the patients without liver failure in addition to encephalopathy, it was not a panacea. Nevens noted that nine of the 34 encephalopathy-only patients developed recurrent ascites or variceal bleeding.

Also, of the 21 patients with post-TIPS liver failure, which Nevens characterized as a form of acute-on-chronic liver failure, only 11 survived through follow-up lasting as long as 5 years, including four who subsequently underwent liver transplantation.

Nevens and colleagues examined several potential risk factors for early mortality in the post-TIPS liver failure group. The most important, and potentially modifiable, was the interval between the original TIPS procedure and the reduction. It averaged 20 days in the fatal cases compared with 10 days in survivors.

"We may not have been aggressive enough" in correcting TIPS in the patients who died," Nevens said. Survivors also tended to be younger and have lower MELD (Model for End-Stage Liver Disease) scores, but not to a great degree, he said.

Embolizing Spontaneous Shunts

The other shunt-related complication in cirrhosis involves hepatic vascular defects that arise spontaneously. Laleman noted that attempting to correct them can carry their own risks, such as the potential for thrombosis and aggravated portal hypertension.

Nevertheless, a number of centers in Europe have begun doing such procedures in selected patients. Laleman, Nevents, and their colleagues surveyed six hepatology centers in the U.K., Spain, and Belgium to ask about their experience.

Responses involved a total of 38 patients for whom the procedure was planned, although it was not carried out successfully in one patient. Patients had been treated as long ago as 1998; mean follow-up was about 23 months.

Techniques included transhepatic or femoral vein access, with coils, matrix materials, or "amplatzer" plugs used to embolize the shunts. About half of the shunts were spleno-renal; others were of the mesentericocaval, periumbilical, and mesentericorenal varieties.

Not only was hepatic encephalopathy successfully eliminated in most patients, at least in the short term, but rates of hospitalization due to the condition were reduced by about three-quarters, both within 100 days of embolization and throughout follow-up.

The procedure also restored functional ability in most patients. Whereas 25% of patients were fully autonomous prior to embolization, 65% were described as autonomous afterward.

Laleman noted that eight patients had complications from the procedure. In seven cases these were mild and easily managed, involving such things as hematoma and skin infections. The one major complication was severe bleeding and shock related to transhepatic access, but Laleman said the patient recovered with no long-term adverse effects.

As with TIPS reduction, the embolization did not solve all the patients' problems. Liver function, as quantified by MELD scores, continued to deteriorate, and portal hypertension persisted in patients who had it prior to surgery.

In a multivariate analysis of risk factors for encephalopathy recurrence, the most important predictive factor was MELD score prior to embolization, Laleman said.

He said a MELD score of 11 or less appeared to be a good cutoff for predicting success, with a sensitivity of 66% and specificity of 78%. The lower MELD score, he said, could be taken as an indicator of "sufficient functional liver reserve."

Both studies had no commercial funding. All authors declared they had no relevant financial interests.

Primary source: European Association for the Study of the Liver
Source reference:
Laleman W, et al. "Embolization of large spontaneous portosystemic shunts for refractory hepatic encephalopathy: A European multi-center survey on safety & efficacy" EASL 2013; Abstract 77.

Additional source: European Association for the Study of the Liver
Source reference:
De Keyzer B, et al. "The outcome of shunt reduction after TIPS by the Parallel Technique: A prospective study" EASL 2013; Abstract 79.

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