Domino Transplant

Provided by Science Daily

Sep. 18, 2013 — Tiffany Schwantes was going to die without a new liver. The 31-year old mother of two suffered from an aggressive form of liver cancer and, because of organ allocation rules, she could not be placed high enough on the liver transplant list to receive a new liver in a timely manner. Surgeons at Houston Methodist Hospital and her oncologist at the University of Texas MD Anderson Cancer Center determined that the only way to save her life was a domino transplant.

This is a rarely performed and complicated procedure that would allow her to receive a new liver from a living donor,” said R. Mark Ghobrial, M.D., director of the Center for Liver Disease and Transplantation at Houston Methodist Hospital.

The majority of patients with her type of cancer, cholangiocarcinoma, never receive a transplant, but Schwantes’ case was different.

“She was young and her tumor was responding to chemotherapy for a sustained duration,” said Milind Javle, M.D., an MD Anderson GI oncologist. “Because of her positive response to treatment I was able to refer her to the Houston Methodist liver transplant team.”

Tiffany was on what is called the ‘out-of-criteria’ list. Her liver was not sick enough for her to receive one from the normal donor pool where recipients are chosen by their degree of illness, said Howard Monsour, M.D., chief of hepatology at Houston Methodist Hospital. “If we would have waited for her liver to deteriorate, her cancer would have spread and she would have never made it.”

Meanwhile, 60-year old Vernon Roberson was suffering from amyloidosis, a genetic blood disease that attacks and destroys organs such as the heart, liver, kidneys, etc. He was progressively getting worse and was in need of a heart and liver transplant. When the organs became available this past July, surgeons asked him if he would be okay with donating his liver to Schwantes.

“I told them if I can save someone’s life, I am all for it,” Roberson said.

“While the diseased liver was not working for Mr. Roberson, we determined it was a viable organ for Tiffany,” Ghobrial said. “It will take her 20 to 30 years to develop amyloidosis, if at all, and if that occurs she can get another liver transplant. This was really the only option for saving her life.”

Ghobrial says more precision is necessary for this surgery than a standard liver transplant because blood flow to the organ must be preserved to keep it viable for the recipient. During a normal procedure, the liver is removed and discarded.

The 12-hour plus procedure involved a large transplant team that included four liver surgeons, two cardiac surgeons, two anesthesia teams, a perfusion team, transplant coordinators and at least 10 nurses.

“This is the first domino transplant we have ever done at Houston Methodist Hospital. It’s a very rare procedure, but I think the shortage of organs will cause us to look at doing more in the future,” Ghobrial said.

“There’s been a national push to use more of these so-called ‘marginal’ organs,” Monsour said. “We have a great joint program with MD Anderson where they are referring more of these patients like Tiffany to us for evaluation. I think if we can catch these cancers early, I believe we can save many more lives by performing domino transplants.”

Roberson is on the road to recovery in Houston and Schwantes is back home in Alabama enjoying life with her husband and children.

“This is a wonderful example of collaboration between different institutions to provide innovative approaches to betterment of human life,” Ghobrial said. “Thinking outside the box, we all helped prolong the life of a young wife and mother. That’s what makes this job so great.”

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Patient Profile: Living With Childhood Hepatitis C

Provided by EverydayHealth.com

A Texas couple shares the story of their child with hepatitis C. Learn about precautions they take as well as treatment that holds the promise of a cure.

By Karen Appold

Medically reviewed by Pat F. Bass III, MD, MPH

When Frances and Terry Perryman, of Spring, Texas, adopted their son Austin, they knew his mother had tested positive for hepatitis C. However, "because only a small percent of children get hepatitis C from their mother, we thought the odds were in our favor," says Frances.

According to the American Liver Foundation, mothers infected with hepatitis C have just a 5 percent chance of infecting their child. What’s more, up to 40 percent of children born with hepatitis C clear the virus on their own before they turn 2.

The couple had Austin tested as a precaution at age 2 and were surprised that their child had the hepatitis C infection. "Although we knew that the possibility existed, our beautiful baby was a picture of health," Terry says.

Hepatitis C, a chronic viral infection of the liver, affects about 0.15 percent of children ages 6 to 11 and 0.4 percent of children ages 12 to 19. An estimated 23,000 to 46,000 children in the United States are living with hepatitis C. Austin is typical — most kids living with hepatitis C were infected at birth.

Austin didn’t have any signs of hepatitis C, which is also typical. Most children living with hepatitis C have no symptoms. "That's what is so scary about this disease," Frances says. "You don't see symptoms until there's significant damage to the liver."

The Perrymans were devastated by the diagnosis. "It's hard to look at a child that you love so much and know that there's something inside him that's making him a little sicker every day," Terry says.

Precautions for Kids Living With Hepatitis C

Children with hepatitis C should take special precautions. If an injury occurs, parents need to make sure that their child’s blood and other bodily fluids don’t come into contact with anyone else. This contact could spread disease, says Austin’s doctor, Daniel Leung, MD, an assistant professor of pediatrics at Baylor College of Medicine and medical director of the Viral Hepatitis Clinic at Texas Children’s Hospital in Houston.

This means that caregivers — even parents — who are helping an injured child who has hepatitis C should wear gloves to prevent exposure.

In addition, Dr. Leung says that a teen or child with hepatitis C should not share toothbrushes, needles, or razors, which can spread hepatitis C. There are no concerns related to living in the same household such as kissing, hugging, or sharing cups or utensils, however.

After learning that their child had hepatitis C, the Perrymans told Austin, now 12, about his diagnosis. "He's fully aware of the precautions that he has to take if he bleeds for any reason," Frances says. "We make sure that we have gloves on hand."

Children living with hepatitis C can participate in any activities they choose. The couple told Austin's baseball coaches about his condition so they can wear protective gloves in case he gets injured on the field.

Success of Treatment for Hepatitis C in Children

Treatment options depend upon the genotype of the child with hepatitis C. In Austin's case, only one type of treatment was available. The first round of Austin's treatment, ribavirin (in liquid form) twice a day and a weekly injection of peginterferon alfa-2b, failed. However, after consulting with his doctor at Texas Children's Hospital, Austin and his parents agreed to try a second round of treatment, using the same drug combination.

Austin has the same side effects adults often experience: He’s fatigued and feverish for 24 to 48 hours after getting the injection, Frances says.

"We've also seen a change in his personality and ability to focus," says Terry, who notes that although Austin is in many advanced school classes, he's had some struggles because of the drugs’ side effects. He's also changed from a chatterbox to a quieter child at school. Three to four times a week, he goes to the school nurse's office to nap.

Austin's blood counts also have to be monitored. His dosage of medication had to be reduced twice because of low white and red blood counts.

"We considered the side effects before starting the second round of treatment," Frances says. "Ultimately, we decided to move forward with the treatment, hoping that the side effects would be more tolerable now than when he gets older."

The choice seems to be working. Austin’s most recent tests found that the hepatitis C virus is undetectable in his blood. He'll remain on treatment for another six months and will be considered cured six months after treatment stops if the virus is still undetectable. "Based on his genotype, we are very optimistic," Terry says.

Last Updated: 09/20/2013

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Patient, Heal Thyself: Solution To Personalised Treatment For Chronic Infections Could Lie In The Patient's Own Blood

Provided by MarketWatch

Sept. 21, 2013, 12:10 a.m. EDT

Singapore, Sept 21, 2013 (ACN Newswire via COMTEX) -- A recent discovery by scientists at A*STAR's Singapore Institute for Clinical Sciences (SICS), in close collaboration with researchers at the Singapore Immunology Network (SIgN), provides hope for a new personalised treatment strategy that could use a patient's own blood to treat the infection. This could help treat millions of people living with chronic infections such as HIV, Hepatitis B or Hepatitis C. These findings were published in the August 2013 issue of The Journal of Clinical Investigation.

Patients suffering from chronic infections often have to undergo long periods of anti-viral drug therapy to control the virus. Anti-viral drugs are not fully effective against viruses such as Hepatitis B and Hepatitis C, which have chronically-infected about 400 million worldwide with more than 1,000,000 people dying from Hepatitis-related diseases every year.[1]

Vaccines are a potentially effective means to treat chronic viral infections such as this because they can eliminate the virus naturally. However, vaccines for patients with chronic infections are often difficult to produce since these patients already have weak immune responses or the vaccine is not effective due to genetic diversity amongst viruses.

The team at SICS led by Prof Antonio Bertoletti has discovered that monocytes, a type of white blood cell that can activate an immune response, are able to capture the virus in chronically-infected patients and use the captured virus to boost the patient's own immune response.

By using the viral antigen already present in the blood of the patient suffering from a chronic illness, this strategy redefines therapeutic vaccines by cutting down on time and resources as there is no need to specially isolate the viral proteins from patients, purify it, and then inactivate it to create a vaccine.

All the proteins present within the virus can be used to create a personalised vaccine for each individual. This also means that many of the complex issues associated with current vaccine therapy against chronic infections can be overcome, such as that of genetic diversity of viruses.

One of the greatest beneficiaries of this discovery would be chronically-infected patient populations in lower socio-economic strata. By tailoring vaccines to be more specific to each virus and each patient, vaccine production can be simplified and thus less costly. Vaccines produced via this discovery could improve the accessibility of such treatments.

Prof Bertoletti said, "Mobilizing the immune system to use the virus within the patient for a vaccine is a simple idea that could lead to a personalised, yet widely applicable, vaccine for chronic infections."

Prof Judith Swain, Executive Director of SICS said, "This excellent collaborative discovery between SICS and SIgN is a milestone in vaccine therapy for chronic infections. I believe that these findings will go a long way in improving future therapeutic treatments for chronic infections."

[1] WHO (ed). WHO | Hepatitis B Fact sheet No 204. WHO. July, 2013.

Notes:

The research findings described in this media release can be found in the August 2013 online issue of The Journal of Clinical Investigation under the title, "Mobilizing monocytes to cross-present circulating viral antigen in chronic infection" by Adam J. Gehring,1, Muzlifah Haniffa,2,3, Patrick Kennedy,4, Zi Zong Ho,1, Carolina Boni,5, Amanda Shin,3, Nasirah Banu,1, Adeline Chia,1, Seng Gee Lim,6, Carlo Ferrari,5, Florent Ginhoux,3, and Antonio Bertoletti,1,7,8.

1. Infection and Immunity Programme, Singapore Institute for Clinical Sciences, Agency for Science Technology and Research (A*STAR), Singapore.

2. Institute of Cellular Medicine, Newcastle University, Newcastle, United Kingdom.

3. Singapore Immunology Network, Agency for Science Technology and Research (A*STAR), Singapore.

4. Center for Digestive Disease, Blizard Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, London, United Kingdom.

5. Unit of Infectious Diseases and Hepatology, Laboratory of Viral Immunopathology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.

6. Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

7. Program Emerging Viral Diseases, Duke-NUS Graduate Medical School, Singapore.

8. Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

About the Singapore Institute for Clinical Sciences (SICS)

Established in 2007, the Singapore Institute for Clinical Sciences (SICS) is a research institute within the Agency for Science, Technology and Research (A*STAR), and its mission is to develop disease-oriented clinical and translational research programmes in key disease areas.

SICS is distinguished by its focus on clinical sciences and the use of innovative approaches and technologies that enable the efficient and effective study of human health and diseases. The clinical scientists in SICS conduct the full spectrum of "bench to bedside" research activities in metabolic diseases (including diabetes, obesity and insulin resistance), pathways to normal growth and development (including cognitive and behavioural development), nutritional sciences as well as in certain viral infectious diseases such as chronic viral diseases.

The institute aims to attract, train and nurture clinician-scientists and to develop joint programs with universities, academic medical centres, government hospitals and research institutes. For more information on SICS, please visit: www.sics.a-star.edu.sg.

About A*STAR

The Agency for Science, Technology and Research (A*STAR) is Singapore's lead public sector agency that fosters world-class scientific research and talent to drive economic growth and transform Singapore into a vibrant knowledge-based and innovation driven economy. In line with its mission-oriented mandate, A*STAR spearheads research and development in fields that are essential to growing Singapore's manufacturing sector and catalysing new growth industries. A*STAR supports these economic clusters by providing intellectual, human and industrial capital to its partners in industry. A*STAR oversees 20 biomedical sciences and physical sciences and engineering research entities, located in Biopolis and Fusionopolis as well as their vicinity. These two R&D hubs house a bustling and diverse community of local and international research scientists and engineers from A*STAR's research entities as well as a growing number of corporate laboratories. For more information about A*STAR, please visit www.a-star.edu.sg.

Source: A*STAR

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Understanding the liver can help keep it healthy

Published: Thursday, September 19, 2013

(Metro) -- The human liver performs an array of functions. In addition to detoxification and protein synthesis, the liver also produces chemicals necessary for digestion. Understanding the role of the liver can help people make smart choices about keeping their livers healthy and avoiding disease.

Understanding the liver

The largest glandular organ of the body, the liver weighs about three pounds and is divided into four lobes of unequal size and shape. The liver can be found in the right side of the abdominal cavity. A healthy liver will be a reddish-brown color.

One of the main functions of the liver is to eliminate harmful biochemical waste products. Much like the kidneys, the liver acts a filter for the body, helping to detoxify alcohol and certain drugs. It also helps clear the body of environmental toxins that may have been ingested.

The liver also produces substances that break down fats. The liver turns glucose to glycogen, which serves as a secondary energy storage in the body. The liver produces urea, the primary compound in urine, and makes certain amino acids, which are the building blocks of proteins.

The liver also produces bile, which aids in the digestion and intestinal absorption of the fat-soluble vitamins A, D, E, and K. Bilirubin is the main bile pigment that is formed from the breakdown of waste substances in red blood cells.

Diseases of the liver

The Centers for Disease Control and Prevention indicate chronic liver disease and cirrhosis is diagnosed in roughly 100,000 patients who visit hospitals each year.

Jaundice is one of the most recognizable warning signs that the liver may not be functioning properly. Jaundice is the yellow coloring of the skin, the sclera in the eyes as well as other mucous membranes. It is caused by hyperbilirubinaemia. If the liver isn't functioning at full capacity, it cannot maintain the correct amount of bilirubin in the blood.

Several behaviors can negatively affect the liver. Drinking too much alcohol can damage liver function over time, and certain drugs -- both pharmaceutical and recreational drugs -- can compromise the liver. Some drugs that treat cancer and diabetes can be harsh on the liver.

Drugs that treat cholesterol can also affect liver function because the liver is also responsible for producing a good amount of the cholesterol in the body. The cholesterol that the liver produces is vital to strengthening the membranes of cells in the body.

Hepatitis is an inflammatory disease of the liver that is caused by a number of different viruses. Hepatitis comes in many forms and is even named A through G, depending on the virus responsible for the infection.

Cirrhosis is scarring that appears on the walls of the liver.

While alcohol consumption is largely blamed for liver disease, it is only one of the many causes. Cancer also can occur in the liver, and liver cancers typically spread through the bloodstream from other areas of the body.

Keeping the liver healthy

Maintaining a healthy liver involves eating a well-balanced diet and drinking plenty of water, which helps to flush toxins out of the body. Foods that are high in fat or sugar can be harder on the liver, and should be consumed in moderation.

People should avoid overconsumption of alcohol and only use drugs as prescribed by a doctor. According to the University of Maryland Medical Center, drinking 10 or more cups of green tea per day was associated with less liver disease in men.

The liver is vital to human health, performing so many functions in the body. So it pays to keep the liver healthy by eating well and avoiding drugs and alcohol.

New test enables early diagnosis of liver cancer

Provided by MedicalXpress

September 19, 2013

by Toni Baker

Drs. Ravindra Kolhe, pathologist and Medical Director of the Georgia Esoteric, Molecular Labs, LLC, at the Medical College of Georgia at Georgia Regents University; Amyn Rojiani, Chairman of MCG's Department of Pathology; Andy Rahardja and Puneeta Vasa, pathology residents. Credit: Phil Jones

Researchers have found a way to make early liver cancer show its true colors. They have developed a test that will help pathologists clearly distinguish early liver cancer cells from nearly identical normal liver cells by giving them a distinctive red-brown hue.

The inability to definitively tell the difference often means the disease is detected late when treatment options are less effective, said Dr. Ravindra Kolhe, pathologist and Medical Director of the Georgia Esoteric, Molecular Labs, LLC, at the Medical College of Georgia at Georgia Regents University.

"There is no definitive test for early diagnosis of liver cancer," said Kolhe, lead author of the study being presented at the American Society of Clinical Pathology 2013 Annual Meeting in Chicago, Sept. 18-21. "Our test adds a level of comfort for making the diagnosis."

"The deadly liver cancer cells seek to recapitulate the appearance of normal liver cells," said Dr. Amyn M. Rojiani, Chairman of MCG's Department of Pathology. And they are very good at that, the pathologists agree, which is the frustration they have when trying to give patients definitive answers from looking at the tiny core biopsies of their liver under the microscope.

"As pathologists, we often find ourselves wanting to know more," said Dr. Andy Rahardja, a pathology resident who worked on the project. "Our test helps us differentiate between the two."

Unfortunately early liver cancer also is mostly silent. By the time it's large enough to cause classic symptoms such as abdominal pain and weight loss, the cancer cells look distinctive but the liver is failing. The myriad of treatment options - from removing the diseased portion of the liver to liver transplants to freezing or heating cancer cells - have a high chance of failing as well, Kolhe said.

"You want to make the correct diagnosis as early in the game as you can," Kolhe said. He began collaborating with BioGenex laboratories, a California company with expertise in cell and tissue testing, to develop a probe that gives cancer cells the distinctive red-brown hue. The probe detects and stains a microRNA called mir-21, which is found in liver cancer but not healthy liver cells, Kolhe said.

Unlike RNA, microRNA doesn't make proteins rather helps control proteins that are expressed by RNA. That means it's more stable and can survive harsh chemicals normally used to prepare the biopsy for microscopic evaluation. This includes using formaldehyde and replacing natural fluids with paraffin so the tissue can be easily cut and stained with different reagents to help pathologists try to pinpoint a patient's problem.

For the study, they used their probe on biopsies of 10 healthy livers and 10 livers with early cancers. In every case of liver cancer, the biopsy took on the red-brown hue. The probe was not detected in normal cells. The studies were done retrospectively, so they already knew which patients ultimately were diagnosed with cancer. They are now using the test on 200 similar cases of liver cancer.

The group also is exploring this approach in other hard-to-detect-early cancers. Kolhe worked with pathology resident Dr. Puneeta Vasa to identify microRNAs selectively expressed in melanoma. Under the microscope, the potentially deadly skin cancer cells look a lot like common mole cells. These findings also will be presented at the American Society of Clinical Pathology meeting and the researchers are working with BioGenex to develop probes to make melanoma-relevant microRNA stand out as well.

In the case of diagnosing early liver cancer, the physicians note that cirrhosis, a massive scarring of the liver resulting from chronic infection with hepatitis B and C viruses, further muddies the current diagnostic waters by essentially giving cancer cells cover. These common viruses are the most common cause of liver cancer worldwide, according to the American Cancer Society. Alcohol abuse, a leading cause of cirrhosis in the United States, also is a risk factor for liver cancer. The new probe fortunately does not interact with cirrhosed cells, Kolhe said.

Explore further: Liver cancer due to chronic inflammation: Tumour growth follows programmed cell death (apoptosis)

Provided by Medical College of Georgia 

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Dermatologic side effects from sorafenib linked to better HCC survival

Provided by Healio

September 18, 2013

Patients with hepatocellular carcinoma who experienced dermatologic side effects while treated with sorafenib had improved survival in a study presented at the International Liver Cancer Association Annual Conference in Washington, DC.

Researchers evaluated data from 147 patients with hepatocellular carcinoma treated with sorafenib for a median of 6.7 months between October 2007 and July 2011. Clinical and laboratory evaluations were performed monthly, with tumor staging after 4 weeks followed by every 8 weeks, for a median follow-up of 11.6 months. Ninety-seven percent of participants had cirrhosis, and 46% were HCV-positive.

Overall, the median time to progression (TTP) was 5.1 months for the cohort; median overall survival was 12.7 months. Dermatologic adverse events that occurred within 60 days of treatment (AED60) were observed in 79 patients, 37 of whom required a sorafenib dose modification.

Although dose modifications were significantly more common among AED60 patients (three modifications vs. two; P=.006), median time to progression (8.1 months vs. 3.9 months; P=.02) and overall survival (18.16 months vs. 10.1 months; P=.009) were better among these participants compared with those who did not experience AED60. No other evaluated categories of early adverse events were associated with treatment outcomes.

Multivariate analysis indicated a significant association between improved survival and any grade of AED60 (P=.039). When cases of early death were excluded from analysis, this association was upheld for incidence of AED60 that required sorafenib dose modification (above grade 1in severity) (P=.03).

“Development of dermatologic adverse events within 60 days of sorafenib initiation is associated with better survival,” the researchers concluded. “Therefore, this should not … discourage treatment maintenance. Likewise, second-line clinical trials should be designed and/or evaluated considering this information to avoid significant bias.”

Disclosure: Researchers Maria Reig, MD, and Alejandro Forner, MD, reported serving as consultants for Bayer Pharmaceuticals.

For more information:

Reig M. O-033: Dermatologic Adverse Events Within the First 60 Days of Sorafenib Treatment Are Associated with Better Overall Survival in Patients with Hepatocellular Carcinoma. Presented at: The International Liver Cancer Association Annual Conference 2013; Sept. 13-15, Washington, DC.

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New mouse model for hepatitis C (Nature)

Princeton Journal Watch 

Princeton University

By Catherine Zandonella, Office of the Dean for Research

Hepatitis C affects about three million people in the U.S. and is a leading cause of chronic liver disease, so creating a vaccine and new treatments is an important public health goal. Most research to date has been done in chimpanzees because they are one of a handful of species that become infected and spread the virus.

Now researchers led by Alexander Ploss of Princeton University and Charles Rice of the Rockefeller University have generated a mouse that can become infected with hepatitis C virus (HCV).  They reported the advance in the Sept 12 issue of the journal Nature. “The entire life cycle of the virus — from infection of liver cells to viral replication, assembly of new particles, and release from the infected cell — occurs in these mice,” said Ploss, who joined the Princeton faculty in July 2013 as assistant professor of molecular biology.

Ploss and his colleagues have been working for some time on the challenge of creating a small animal model for studying the disease. Four years ago, while at the Rockefeller University in New York, Ploss and Rice identified two human proteins, known as CD81 and occludin, that enable mouse cells to become infected with HCV (Nature 2009). In a follow up study Ploss and colleagues showed that a mouse engineered to express these human proteins could become infected with HCV, although the animals could not spread the virus (Nature 2011).

In the present study, which included colleagues at Osaka University and the Scripps Research Institute, the researchers bred the human-protein-containing mice with another strain that had a defective immune system – one that could not easily rid the body of viruses. The resulting mice not only become infected, but could potentially pass the virus to other susceptible mice.

The availability of this new way to study HCV could help researchers discover new vaccines and treatments, although Ploss cautioned that more work needs to be done to refine the model.

The study was supported in part by award number RC1DK087193 from the National Institute of Diabetes and Digestive and Kidney Diseases; R01AI072613, R01AI099284, and R01AI079031 from the National Institute for Allergy and Infectious Disease; R01CA057973 from the National Cancer Institute; and several foundations and contributors, as well as the Infectious Disease Society of America and the American Liver Foundation.

Read the abstract

Marcus Dorner, Joshua A. Horwitz, Bridget M. Donovan, Rachael N. Labitt, William C. Budell, Tamar Friling, Alexander Vogt, Maria Teresa Catanese, Takashi Satoh, Taro Kawai, Shizuo Akira, Mansun Law, Charles Rice & Alexander Ploss. 2013. Completion of the entire hepatitis C virus life cycle in genetically humanized mice. Nature 501, 237–241 (First published online on 31 July 2013)  doi:10.1038/nature12427.

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3 Companies Racing to Transform Hepatitis-C Treatment

Provided by DailyFinance

by Keith Speights, The Motley Fool Sep 18th 2013 7:00PM
Updated Sep 18th 2013 7:02PM

Imagine a line of adults lying on the ground stretching from Los Angeles to the Atlantic coast of Maine. That number of people, around 3.2 million, represents how many Americans are estimated to have chronic hepatitis-C.  

Many individuals affected by chronic hep-C must take antiviral medications via injection that can cause side effects including flu-like symptoms. That could be changing in the not-too-distant future, though. Several companies are racing to develop an all-oral regiment for hepatitis-C that could transform how the disease is treated. Here are three leaders in this race.

1. Gilead Sciences
At this point, Gilead appears to be able to claim front-runner status. The biotech awaits a decision by the U.S. Food and Drug Administration on or before Dec. 8 regarding approval of sofosbuvir in combination with ribavirin as an all-oral treatment for hep-C genotypes 2 and 3. However, the big prize is getting to market with an oral regimen for genotype 1, which accounts for around 75% of all hep-C patients.

Gilead shouldn't be too far off in jumping that hurdle. The biotech has late-stage studies under way, with sofusbuvir combined with both ribavirin and its own ledipasvir. Mid-stage results for the combo were very impressive, with a 95% cure rate after eight weeks of treatment.

Unless unforeseen problems emerge, Gilead seems poised to reach the market first with its all-oral regiment for hep-C genotype 1. The company hopes to market the sofusbuvir/ledipsasvir combo next year.

2. AbbVie
If AbbVie has anything to say about it, though, Gilead won't be the first to market. Scott Brun, the company's VP of pharmaceutical development, recently stated that he thinks AbbVie has "a very good shot at being first."

Brun's optimism stems from success that AbbVie has had with its own all-oral combo. Results from mid-stage studies showed that the company's antiviral combination of drugs achieved a 99% cure rate in treatment-naive patients and a 93% cure rate in all responders after 12 weeks.

Like Gilead, AbbVie currently has late-stage studies under way. Also like Gilead, the company hopes to be on the market with its drug combo in 2014. As Brun noted, "it is a very tight race."

3. Bristol-Myers Squibb
Regardless of which company wins that race, chances are that they won't share the market between just the two of them for long. Bristol-Myers Squibb doesn't trail too far behind with its all-oral regimen including daclatasvir, asunaprevir, and BMS-791325.

In April, Bristol announced positive phase 2 results for the combo. Up to 94% of patients were cured of hepatitis C after 24 weeks of treatment.

Bristol is now in phase 3 testing of the three-drug combo. The likelihood for now appears to be that the big drugmaker will reach the market several months after Gilead and AbbVie.

Winners
It isn't out of the question that all three of these companies could ultimately prove to be marketplace winners. The overall hepatitis-C market size is pegged to be around $20 billion. That pie will be split somehow, although how big each slice is remains to be seen.

Gilead probably stands the best shot at becoming the biggest winner. The biotech should hit the market first with its treatment (even if only barely). More importantly, there's a convenience factor that could help the sofusbuvir/ledipsasvir combo. While AbbVie's regimen requires patients to take three pills in the morning and another pill in the evening, patients taking Gilead's combo will probably only have to take one pill once per day.

This race isn't limited to Gilead, AbbVie, and Bristol. Several of other companies have other drugs a little further behind in the development cycle. Johnson & Johnson , for example, teamed up with Idenix to develop an all-oral regimen. The two companies, along with J&J's partner, Medivir, kicked off a mid-stage study of samatasvir combined with simeprevir in May. 

The intensity of the competition ultimately means that the biggest winner of all won't be any of these companies. That honor belongs to the millions suffering from hepatitis-C -- from Los Angeles to Maine and around the world.

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The article 3 Companies Racing to Transform Hepatitis-C Treatment originally appeared on Fool.com.

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Viral Hepatitis: Patients’ Perspective in Ghana

Provided by GhanaWeb

Feature Article of Thursday, 19 September 2013

Columnist: Owusu-Ansah, Theobald

I am honoured to speak on viral hepatitis from the perspectives of patients in Ghana. Viral hepatitis is a silent and under-estimated public health problem worldwide, and which is particularly endemic in the Sub-Saharan Africa and Ghana. Hepatitis B is a preventable disease.

Thousands of Ghanaians live with viral hepatitis. About a third of Ghanaians living with viral hepatitis are unaware of their status and are not receiving care and treatment for the condition. Raising awareness about hepatitis is crucial to effectively fight stigmas, stem the tide of new infections, and ensure treatment reaches those who need it. On World Hepatitis Day, we join others across Ghana and around the world in promoting strategies that will help save lives and prevent the spread of viral hepatitis.

“Hepatitis” means inflammation of the liver. It refers to a group of viral infections that affect the liver. There are five main hepatitis viruses, referred to as types A, B, C, D, and E. The most common types are the A, B, and C.

Ladies and Gentlemen, nearly one out of every three people in the world (approximately 2 billion people) has been infected by the hepatitis B virus (HBV), and one in twelve (more than 520 million people) live with chronic HBV or/and hepatitis C (HCV) infection. In Ghana, hepatitis is the leading infectious cause of death, claiming the lives of thousands of Ghanaians each year. While we have come thus far in containing the spread of the virus, much more work is still needed to be done in treating and managing the disease.

Viral hepatitis affects Ghanaians of all backgrounds, but certain groups are at a greater risk than others. Before blood was screened for viral hepatitis many who received blood transfusion were infected, infants born to mothers infected with the viral hepatitis, and persons with multiple sex partners or indulge in certain behaviours such as injection of drugs, tattooing and tribal marks have a higher risk of infection.

Carriers of viral hepatitis in Ghana face many social and economic challenges. Ladies and Gentlemen, the social impact of hepatitis on carriers are numerous but because time is not on my side, I will focus on but a few:

Social effects on patients

Sexual Activity: Many viral hepatitis patients in Ghana are fearful of engaging in sexual activities once they are diagnosed with the virus. They are concerned about passing the virus onto their partners, and as a result, many marriages are not consummated and relationships are broken. But research shows that sexual activity can benefit one’s immune system. Sexual activity triggers the release of endorphin, which helps create a more positive attitude. It also helps one to forget about his/her problems. Thus, sexual activity can go a long way to enhance the healing process and creating an environment for a better functioning of one’s immune system. Carriers of the viral hepatitis living with one long-term sexual partner do not need change their sexual habits and practices. However, those with more than one sexual partner should practice safe sex by using condom.

Stigmatization: There is a societal stigma about hepatitis. Infected people are alienated by society. Individuals may also be isolated within their families, hidden away from visitors or made to eat alone. Many carriers are refused access to educational facilities and there is as a result a high prevalence of school dropout and illiteracy. They are looked down upon for contacting the virus, as it is generally to be associated with sexual promiscuity. Because society ignores their plight some carriers choose to revenge on society by spreading the virus through indiscriminate sexual activities.

Difficulties in accessing medical care: Many health centres in Ghana are not well equipped to handle viral hepatitis cases and the technical know-how of some medical doctors and other healthcare professionals in treating the condition is limited. As a result, many patients do not get diagnosed and do not get referred to receive appropriate medical attention that they may need.

Low self-esteem: Many carriers of the virus suffer a great loss of self-esteem once diagnosed. Because of the lack of knowledge about the disease, many away even from close relatives, withdraw from society and can no longer participate in public activities. Low self-esteem can bring depression, which can lead one to commit suicide. Many people living with the chronic viral hepatitis in Ghana become depressed as a result blaming themselves. They find it very difficult to tell their partners or family members because getting infected by the viral hepatitis is usually associated with indulging in sexual activities.

Beliefs: Some people see the viral hepatitis as a curse. There is a traditional belief that viral hepatitis is a spiritual disease. It is also believed that viral hepatitis is hereditary so if one’s parents are infected, it is automatically thought that children will also be infected. Most patients also believe that viral hepatitis is not treatable.

Stress: Carriers of the virus are always stressed up because of the factors I just numerated earlier. Stress can suppress the immune system, which may cause patients to be more vulnerable to other diseases. The stress may be compounded by the fact that one may never know how, when, or where the infection occurred since most people are not diagnosed until well after the initial infection. Asking questions and trying to understand as much as one can about Hepatitis B can also go a long way toward reducing one’s stress level. Without knowledge you run the risk of having your decision controlled by fear and misinformation.

Breastfeeding: Breastfeeding mothers are always fearful of transmitting the virus to their newborn babies. Some mothers will not breastfeeding their babies at all, which is dangerous because the breast milk is good for the baby to grow well. It is always advisable to inform one’s nurse when one is going for antenatal care, the nurse will give your baby a shot called H-BIG and a shot of hepatitis B vaccine within 12 hours after birth. After the baby has been vaccinated on delivery, it is alright to breastfeed the baby. The viral hepatitis is not transmitted through breast milk! It is important to take good care of your nipple areas to prevent cracking and bleeding.

Marriage: Many people are fearful of getting married or telling their partners of their status. Some people also think that they may lose their partners if they tell them so they will not tell. Is advisable to inform your partner before getting married, if he/she gets to know of it? Yes, it is always a good idea to let your partner know of one’s status before marrying so that the would-be partner can get vaccinated

Life Span: There is no life span for hepatitis patients, you can live as many years as God wants you to live when you treat it and monitor it well. Many patients are fearful of death so those who call always want to know the number of years they have on earth or to know the time they will die. “Say no to ignorance.”

Ladies and Gentlemen, I will now focus on the economic impact of hepatitis on individuals, families and the national economic development and growth.

Economic effects on patients

Household Income: The incomes of carriers of the viral hepatitis may also be affected because carriers may not be able to work at their full capacity and/or even holding down permanent job.

Basic Needs: Most carriers have to constantly cut their spending on basic necessities of life .The most likely expenses to be cut are clothing, electricity, food, shelter and other services. The cost of medical treatment means that most of their already reduced income is spent on medical care.

Termination of Employment: People living with chronic viral hepatitis have to visit the hospital regularly, which costs their employers thousands of cedis in medical bills and time away from the workplace. As a result, employments of many carriers are employments of many carriers are often terminated.

The Way Forward

Counseling:
• Counseling should be an integral part of any medical model when treating carriers of viral hepatitis.
• A holistic approach should be adopted by medical doctors and allied healthcare professionals in treating carriers so that their psychological needs can be recognized.
• Adequate support should be given when one is diagnosis or the first time, as patients do experience great stresses due to fear of the disease and of rejection and social stigma that are associated with the disease.

Confidentiality: Confidentiality is as important for viral hepatitis patients as it is for all other patients. All healthcare professionals should treat the cases of their patients with the strictest confidentiality, particularly with regards to:
- Medical records
- Staff confidentiality
- Partner/family notification and disclosure

Screening facilities: Screening facilities should be provided at all local health centres, district polyclinics, and regional government hospitals (e.g. all pregnant women should be tested).

Prevention tools: Precaution should be exercised regarding injection safety, blood safety and immunization of all new born as well as vaccination of all healthcare professionals.

Continuing care: Ensuring that those already infected with the virus have timely access to care, and effective and affordable treatments to delay development of the disease and prevent disability and eventual death.

Disease surveillance: Strengthening disease surveillance, such as establishing national database to monitor spread of the virus in order to establish patterns of progression would be a step in the right direction.

National awareness: Increasing national awareness of viral hepatitis through the commemoration of a World Hepatitis Day on 28 of July every year, as Member States agreed to do at the 63rd World Health Assembly in Geneva on 21 May, 2010.

Ladies and Gentlemen, we must make sure that this "silent epidemic" does not go unnoticed by health professionals or by communities across our country. Our goal is to reduce the number of new infections, increase status awareness among people living with virus, and eliminate the transmission of viral hepatitis from mothers to their children.

The first step toward achieving these goals is to raise public awareness of this life-threatening disease. We must work to reduce the social stigma of the virus, and to ensure that testing, information, counseling, and treatment are available to all who need it. The hard work and dedication of healthcare professionals, researchers, and advocates will help bring us closer to these goals. On this day, we renew our support for those living with the viral hepatitis, and for their families, friends, and communities who are working to create a brighter, healthier future for all!

For counsel and advice on treatment and management, Contact us. Support our work to spread the word but not the virus.

Theobald Owusu-Ansah
President, Theobald Hepatitis B Foundation
President, Hepatitis Coalition of Ghana
Regional Board Member for Africa, World Hepatitis Alliance, UK
Board Member, National Association of Hepatitis C Taskforce, USA
Email: theobald2003@yahoo.com/  president@theobaldhepb.org
Web: www.theobaldhepb.org  . Tel: +233 (24) 709-3893 / +233-26-8269214

Source

Hepatitis: Understanding the Enemy

By Abdul-Lateef Balogun

Freelance Writer - Malaysia

Wednesday, 18 September 2013 00:00

1 in every 12 people is living with Hepatitis, and the majority of those infected are unaware of their status.

According to the World Hepatitis Alliance, globally, one in every 12 people is living with hepatitis, and the majority of those infected are unaware of their status.

Ironically, despite its higher occurrence rate, not much is known by the general public about this disease when compared with less prevalent diseases such as cancer and AIDS.

For a disease that claims an approximated 1.5 million lives annually, hepatitis certainly deserves much more attention than it is presently getting.

Knowing the Enemy

Hepatitis simply means inflammation of the liver and it can be caused by various types of hepatitis viruses that lead to the destruction of liver tissue. There are seven known types of viral hepatitis, and their causes, symptoms and cures vary. Hepatitis A virus (HAV) is the most common cause of viral hepatitis and can be found in the feces of those infected. (Magee)

Many people become infected with HAV by eating or drinking contaminated food or drink, and it is a popular disease in developing countries where sanitation and sewage infrastructure is poor. Hepatitis A is the cause of approximately 100 deaths perآ year in America (HFI).

Hepatitis B is a type of liver inflammation caused by the hepatitis B virus (HBV) that triggers medical complications such as cirrhosis (scarring of the liver), and in some people liver cancer. If left untreated, this disease can lead to chronic long-term illness.

According to Jodie Walton, the health promotion officer at Queensland's Hepatitis Council in Australia, "Hepatitis B and C are chronic health conditions that can cause long term health problems. Other strains D, E, F are less likely to cause any major health problems."

People are more likely to get the virus if they receive unsterile body piercings, tattoos or even the increasingly utilized acupuncture

Discussing the forthcoming World Hepatitis Day event, she explained to IslamOnline.net that even Hepatitis A, which is a short-term disease, has the potential to cause severe sickness. While adults who are infected usually recover, most infants infected at birth become chronic carriers and even spread the infection (WHO).

Both HAV and HBV are regarded as sexually transmitted diseases (STD) as they can also be transmitted via unprotected sex with an infected person.

Hepatitis C is perhaps the most worrisome viral hepatitis because there is no known vaccine for it. "Vaccination research is being conducted for hepatitis C, but it is unlikely that we will ever get a vaccination for hepatitis C that is as effective as the hepatitis B vaccine," said Walton.

For a disease that can affect virtually anyone, it is definitely important to be aware of its various modes of transmission in order to avoid it. "Anyone can be affected by hepatitis; we see young and old people, male and female, affected by it from all walks of life," she explained.

Just like AIDS, hepatitis is often spread through blood contact. People are more likely toآ become infected withآ the virus if they receive unsterile body piercings, tattoos or even the increasingly utilized acupuncture. Sharing contaminated needles or other drug injecting paraphernalia can also lead to infection, as can blood and blood product transfusions in countries where blood is not carefully screened for blood-borne viruses.

Apart from such generic causes, hepatitis B can also spread from infected mothers to their children during pregnancy or childbirth. While it is possible to avoid these modes of transmission, it is rather unfortunate that not all types of hepatitis are preventable, although they can still be managed if detected early enough.

Another form of hepatitis that is not caused by a virus is autoimmune hepatitis, a form of hepatitis that occurs when the body's immune system, which is supposed to protect it from pathogens, begins to attack liver cells, thereby, causing inflammation of the liver. The majority of such patients are women, and the disease can last for a long period if not detected and treated early on. (NDDICa)

Tackling the Problem

One major problem with combating hepatitis is that many times, it appears with mild symptoms, which can be easily ignored. In some cases, there are no symptoms at all and this accounts for the large number of people who are infected with the disease rather unknowingly and live normal lives, or so it seems.

However, when symptoms are apparent, they are similar in most types of viral hepatitis. Some of the most common symptoms include: nausea, vomiting, diarrhea, loss of appetite, weight loss, itchy skin, jaundice and abdominal pain. In autoimmune hepatitis, skin rashes, joint pain and the appearance of abnormal blood vessels on the skin may also be observed.

"Prevention is better than cure," is a very popular axiom in medical circles, and this also applies to dealing with hepatitis. By avoiding the common mediums of transmission i.e. exposure to blood or body fluids of infected persons, the chances of infection are drastically reduced. "To prevent hepatitis C, never share blood and never share drug injecting equipment," warned Walton.

Adopting a decent lifestyle, devoid of indiscriminate sex will also lower the chances of infection. It is interesting to note that not all types of hepatitis require serious medical attention.

Hepatitis A and E are likely to resolve on their own without medical intervention within a period of 2-4 months and once the immune system effectively fights off HAV, the person becomes permanently immune to it (NDDICb). This is in addition to the fact that Hepatitis A immunization, administered through a series of injections can prevent an infection for up to 10 years.

"It is unlikely that we will ever get a vaccination for Hepatitis C that is as effective as the Hepatitis B vaccine," said Walton.

Similarly, vaccines are available to protect people against hepatitis B, and it is essential that all newborns of hepatitis B infected mothers be immunized against the virus at the time of birth. There are no vaccines available for hepatitis C, D or E, and limiting exposure to the viruses ultimately provides the best form of protection.

For people who have previously been exposed to any of the likely transmission modes, it is necessary to visit a doctor for comprehensive tests in order to ascertain their condition and if needed to get prompt medical attention before it is too late.

Ignorance Fuelling Hepatitis

It is commonly said that ignorance is a disease of its own, and widespread ignorance regarding hepatitis is one of the major factors militating against the control of this potential time bomb. It is amazing that some people still believe it can be transmitted through physical contact with an infected person. "Hepatitis B or C cannot be spread through touching, hugging, kissing, sharing food, or bathrooms," affirmed Walton.

"Unfortunately, many people tell us they experience stigma. Hepatitis is just a chronic health condition like many others such as diabetes or asthma, not a reason to fear someone or treat them differently," she added. If people are stigmatized they become isolated, irritable, and depressed, so it is very important for people with hepatitis to get appropriate support.

Recently, the Hepatitis Foundation International revealed that the hepatitis B virus is 100 times more infectious than HIV (the AIDS causing virus), and an estimated 350 million people are infected globally. Despite its high prevalence, not much attention is being given to it when compared with less prevalent diseases such as AIDS and cancer that enjoy lots of publicity.

"In Australia, we have had large campaigns surrounding HIV/AIDS and cancer. The community has a good understanding of these health conditions; they have also been well funded by governments around the world," noted Walton.

"Hepatitis is just beginning to change from a stigmatized disease to a chronic health condition needing just as much care and attention," she added.

Speaking further on the issue, she confirmed that the situation is getting brighter as a result of the collective efforts of various international movements, though there is still a long way to go if the present alarming infection rate is to be reduced.

With researchers still working hard to come up with effective treatment options for patients, the best thing people can do is to get educated about hepatitis and learn how to prevent its transmission.

For those already infected, their situation is quite redeemable. "We advise all people affected by hepatitis to avoid contact with alcohol, which is highly toxic to the liver; get regular exercise; eat a healthy diet and avoid stress. If people do these things they can manage their hepatitis and live well," assured Walton.

References

"Autoimmune Hepatitis." National Digestive Diseases Information Clearing House (NDDICHa). April, 2008. Accessed 18 May 2009.

"Hepatitis." World Health Organization (WHO). Accessed 18 May 2009.

Magee, James. "Hepatitis A, Hepatitis B and Hepatitis C." avert.org. 20 Feb. 2009. Accessed 18 May 2009.

"The ABC's of Hepatitis." Hepatitis Foundation International (HFI). 2003. Accessed 18 May 2009.

"Viral Hepatitis: A through E and Beyond." National Digestive Diseases Information Clearing House (NDDICHb). May 2003. Accessed 18 May 2009.

Source

HIV Does Not Affect Chance of HCV Genotype 2 or 3 Responding to PegIFN/RBV

Provided by NATAP

53rd ICAAC Interscience Conference on
Antimicrobial Agents and Chemotherapy
September 10-13, 2013, Denver CO

53rd ICAAC, September 10-13, 2013, Denver

Mark Mascolini

Two thirds of people with HCV genotype 2 or 3 in an Italian single-center study responded to pegylated interferon plus ribavirin (PegIFN/RBV), and HIV infection did not independently affect chances of a sustained virologic response (SVR) in multivariate analysis [1].But HIV/HCV-coinfected people were more likely than people infected only with HCV to have advanced (F4) fibrosis, and advanced fibrosis independently lowered SVR chances

Infection with HCV genotype 2 or 3 responds to PegIFN/RBV more often than genotype 1 or 2 infection. Because little is known about how HIV coinfection may affect chances of SVR in people with type 2 or 3 infection, researchers at an infectious disease center in Brescia, Italy conducted this retrospective analysis of adults infected with those genotypes and starting a first course of PegIFN/RBV between 2005 and 2010.

Study participants took PegIFN/RBV for 48 weeks, but HIV-negative people could stop at week 24 if they had a rapid virologic response or began treatment with fibrosis stage F0 to F2 or an HCV load below 500,000 IU/mL. All HIV-positive patients could use growth factor, but only cirrhotic HIV-negative people could use growth factor. Ribavirin dose could be reduced in any patient if hemoglobin fell despite erythropoietin, if the white cell count remained below 750 in people without HIV, or if the white count fell in an HIV-positive person taking growth factor. Everyone had a Child-Pugh score at or below A5.

Of the 740 study participants, 113 (15%) had HIV and 627 did not. Of the 113 people with HIV, 5% had genotype 2 and 95% had genotype 3. Proportions with genotype 2 and 3 in the HIV-negative group were 45% and 55%. The HIV group included a lower proportion of women (15% versus 36%, P < 0.0001), had lower average body mass index (23.8 versus 25.1 kg/m(2), P = 0.004), and had lower platelet counts (163,200 versus 208,400, P < 0.0001). A lower proportion of HIV-positive than negative people had a pretreatment HCV load above 500,000 IU/mL (33% versus 51%, P = 0.0004). And a significantly higher proportion of people with HIV had F4 fibrosis (23% versus 5%, P < 0.0001).

A moderately but significantly lower proportion of people with than without HIV attained SVR (58% versus 67%, odds ratio [OR] 1.5, 95% confidence interval [CI] 1.0 to 2.2, P = 0.02). Among HIV-positive nonresponders, 15% never had a virologic response, 50% responded and relapsed, and 35% stopped for any other reason. Respective percentages in the HIV-negative group were similar: 16%, 45%, and 40%. Among all study participants, a significantly higher proportion of people with HCV genotype 2 than genotype 3 attained SVR (71.7% versus 61%, OR 1.6, 95% CI 1.1 to 2.2, P = 0.001).

A significantly higher proportion of people with than without HIV had neutropenia during treatment (42% versus 12%, OR 1.3, 95% CI 1.2 to 2.2, P = 0.04), and a significantly higher proportion used growth factor (41% versus 4%, OR 1.2, 95% CI 1.1 to 3.3, P = 0.0005). A much lower proportion of HIV-positive people interrupted PegIFN (9% versus 68%, OR 0.2, 95% CI 0.1 to 0.3, P < 0.0001). Anemia rates did not differ significantly between people with and without HIV (12% and 10%), but a significantly lower proportion of HIV-positive people used erythropoietin (2% versus 16%, OR 1.5, 95% CI 1.1 to 2.6, P = 0.04).

Logistic regression analysis determined that HIV coinfection did not affect chances of SVR (adjusted odds ratio [aOR] 1.0, 95% CI 0.5 to 1.7). Age over 45, gender, F0 to F2 fibrosis, and genotype 3 versus 2 also had no impact on chances of SVR. Ribavirin dose reduction doubled chances of SVR (aOR 2.2, 95% CI 1.3 to 3.8, P = 0.003). Advanced (F4) fibrosis, high pretreatment HCV load, and PegIFN interruption all lowered chances of SVR at the following adjusted odds ratios (and 95% CIs):

-- F4 fibrosis: aOR 0.4 (0.2 to 0.7), P = 0.004
-- Pretreatment HCV RNA above 500,000: aOR 0.6 (0.4 to 1.0), P = 0.03
-- PegIFN interruption: aOR 0.2 (0.1 to 0.3), P < 0.0001

The Brescia team cautioned that their sample size, especially people with HIV, is small. They suggested that failure of HIV infection to affect chances of SVR in multivariate analysis could reflect (1) longer treatment duration in everyone with HIV and (2) frequent use of growth factor to keep HIV-positive people on treatment at the highest dose. The researchers noted that the HIV group had a higher proportion with F4 fibrosis and that F4 fibrosis cut chances of SVR 60%.

The investigators argued that treating HIV/HCV-coinfected people, particularly those with genotype 2 or 3, "remains mandatory."

Reference

1. Nasta P, Giralda M, Chiari D et al. Higher rate of sustained virological response in patients with HCV genotype 2 or 3 infection regardless HIV infection. 53rd ICAAC. September 10-13, 2013. Denver. Abstract H-1528.

Continue here to view posters ……

ABT-450 combined with ritonavir, in addition to ABT-333 and ribavirin: A race for an interferon-free regimen to cure HCV infection

Journal of Hepatology
Volume 59, Issue 4 , Pages 885-888, October 2013

Tarik Asselah

Received 11 March 2013; received in revised form 15 May 2013; accepted 15 May 2013. published online 28 May 2013.

Abbreviations: DAA, direct-acting antivirals, PegIFN, pegylated interferon, SVR, sustained virological response, eRVR, extended rapid virological response, RVR, rapid virologic response

Keywords: Direct-acting antivirals, Sustained virological response, Chronic hepatitis C, NS5A inhibitors, Safety, Resistance

COMMENTARY ON:

Exploratory study of oral combination antiviral therapy for hepatitis C. Poordad F, Lawitz E, Kowdley KV, Cohen DE, Podsadecki T, Siggelkow S, Heckaman M, Larsen L, Menon R, Koev G, Tripathi R, Pilot-Matias T, Bernstein B. N Engl J Med. 2013 Jan 3;368(1):45-53. Copyright © 2012 Massachusetts Medical Society. Abstract reprinted with permission from Massachusetts Medical Society. http://www.ncbi.nlm.nih.gov/pubmed/23281975

Abstract. Background: There is a need for interferon-free treatment regimens for hepatitis C virus (HCV) infection. The goal of this study was to evaluate ABT-450, a potent HCV NS3 protease inhibitor, combined with low-dose ritonavir (ABT-450/r), in addition to ABT-333, a nonnucleoside NS5B polymerase inhibitor, and ribavirin, for the treatment of HCV infection.

Methods: We conducted a 12-week, phase 2a, open-label study involving patients who had HCV genotype 1 infection without cirrhosis. All patients received ABT-333 (400mg twice daily) and ribavirin (1000 to 1200mg per day) and one of two daily doses of ABT-450/r. Groups 1 and 2 included previously untreated patients; group 1 received 250mg of ABT-450 and 100mg of ritonavir, and group 2 received 150mg and 100mg, respectively. Group 3, which included patients who had had a null or partial response to previous therapy with peginterferon and ribavirin, received daily doses of 150mg of ABT-450 and 100mg of ritonavir. The primary end point was an undetectable level of HCV RNA from week 4 through week 12 (extended rapid virologic response).

Results: A total of 17 of the 19 patients in group 1 (89%) and 11 of the 14 in group 2 (79%) had an extended rapid virologic response; a sustained virologic response 12 weeks after the end of treatment was achieved in 95% and 93% of the patients, respectively. In group 3, 10 of 17 patients (59%) had an extended rapid virologic response, and 8 (47%) had a sustained virologic response 12 weeks after therapy; 6 patients had virologic breakthrough, and 3 had a relapse. Adverse events included abnormalities in liver-function tests, fatigue, nausea, headache, dizziness, insomnia, pruritus, rash, and vomiting.

Conclusions: This preliminary study suggests that 12 weeks of therapy with a combination of a protease inhibitor, a non-nucleoside polymerase inhibitor, and ribavirin may be effective for treatment of HCV genotype 1 infection. (Funded by Abbott; ClinicalTrials.gov number, NCT01306617.)

Introduction

Two direct-acting antivirals (DAAs), telaprevir and boceprevir, are given in combination with pegylated interferon (PegIFN) and ribavirin to genotype 1 HCV infected patients. PegIFN has several side effects and many patients are not eligible or have failed this treatment. Therefore, there is a need to develop an IFN-free regimen. Ideally, the future IFN-free regimen should have a high efficacy, favorable safety profile, and high barrier to resistance [1]. This article is discussing the impressive data from the IFN-free trial with ABT-450 based regimen [2], [3].

ABT-450 is an inhibitor of NS3/4A protease that is metabolized by cytochrome P450 isoform 3A (CYP3A). ABT-450 is co-administered with ritonavir (ABT-450/r), a CYP3A inhibitor, to enhance ABT-450 exposure. ABT-450/r is dosed once daily. ABT-267 is an NS5A inhibitor that is dosed once daily. ABT-333 is an NS5B polymerase non-nucleoside inhibitor dosed twice daily.

ABT-450 boosted with ritonavir (ABTr), in addition to ABT-333, and ribavirin for HCV genotype 1 infected patients (pilot and co-pilot studies)

Study design 

Impressive results were reported recently from a phase 2a multicenter open-label study [2]. Groups 1 (n=19) and 2 (n=14) included naïve patients, and group 3 (n=17) included null (n=7) or partial responders (n=10) to previous therapy (Fig. 1A). All patients received triple therapy with ABT-450r, ABT-333, and ribavirin, for 12 weeks.

Fig. 1. Trial designs and results of studies with ABT-333 based regimen. (A) Phase 2a, multicenter, open-label, trial design [2]. All patients received ABT-333 (400mg twice daily) and ribavirin (1000–1200mg per day) and one of two daily doses of ABT-450/r. Groups 1 and 2 included previously untreated patients; group 1 received 250mg of ABT-450 and 100mg of ritonavir, and group 2 received 150mg and 100mg, respectively. Group 3, which included patients who had had a null (n=7) or partial response (n=10) to previous therapy with PegIFN/ribavirin, received daily doses of 150mg of ABT-450 and 100mg of ritonavir. ABT-450, NS3 protease inhibitor, boosted with ritonavir (ABT-450/r); ABT-333, non-nucleoside NS5B polymerase inhibitor. (B) Phase 2a, multicenter, open-label, trial results [2]. A total of 17 of the 19 patients in group 1 (89%) and 11 of the 14 in group 2 (79%) had an extended rapid virologic response; an SVR 12weeks after the end of treatment was achieved in 95% and 93% of the patients, respectively. In group 3, 10 of 17 patients (59%) had an extended rapid virologic response, and 8 (47%) had an SVR 12weeks after therapy; 6 patients had virologic breakthrough, and 3 had a relapse. HCV RNA<LDQ_{TD or TND} (<25IU/ml); eRVR=extended rapid virological response defined as undetectable HCV RNA from week 4 through week 12.

End points 

The primary end point was the percentage of patients with undetectable HCV-RNA from week 4 through week 12 (extended rapid virologic response, eRVR). Secondary end points included patients with HCV-RNA below 25IU/ml at week 4 (rapid virologic response, RVR), at week 12, and 12weeks after the end of treatment (sustained virologic response (SVR)). SVR12 has been demonstrated to be as relevant as SVR24 under PegIFN/ribavirin [4]. COBAS TaqMan HCV Test, version 2.0 was used, with a lower limit of quantitation of 25IU/ml and a lower limit of detection of 15IU/ml.

Efficacy in naïve patients 

17/19 patients in group 1 and 11/14 in group 2 had an eRVR (Fig. 1B). None of the patients in group 1 or 2 had virologic breakthrough and none who completed treatment had a relapse; all patients who completed treatment had an SVR12. All 18 patients who completed treatment in group 1 had undetectable HCV RNA 48weeks after treatment. 2/13 patients who completed treatment in group 2 discontinued the study after week 12 of follow-up; the other 11 patients had undetectable HCV 48weeks after treatment.

Efficacy in patients with null or partial response to previous therapy 

6 patients had virologic breakthrough during treatment, including 1 who mistakenly took only 50mg of ABT-450 daily for the first 3weeks and who never had an HCV RNA lower than 25IU/ml. Ten patients had an eRVR. Three patients had a relapse 2weeks after treatment, and 8 had an SVR12. 3/7 patients with a null response and 5/10 with a partial response had SVR12. In most cases, virologic failure was associated with the emergence of variants with substitutions in both NS3 and NS5B, at positions known to confer resistance in vitro to ABT-450 and ABT-333, respectively.

Safety

No deaths or serious adverse events occurred. One patient in group 1 discontinued drugs owing to aminotransferases increase at week 2. The elevated aminotransferase levels were not associated with an increased bilirubin level and improved after treatment. The most frequent events were fatigue, nausea, headache, dizziness, insomnia, pruritus, rash, and vomiting. Most events were mild. Four adverse events were classified as severe: fatigue, pain, vomiting, and hyperbilirubinemia. None of these events led to drug discontinuation.

ABT-450/r, ABT-267, ABT-333 and ribavirin (Aviator study) 

The Aviator phase 2b study assesses the safety and efficacy of ABT-450/r, ABT-267 (NS5A inhibitor), ABT-333, and ribavirin in non-cirrhotic naïve patients and prior PegIFN/ribavirin null-responders for 8, 12 or 24weeks (Fig. 2A) [3]. Results are summarized in Fig. 2B. For the 12-week triple-DAA regimen with ribavirin being studied in phase 3 trials: 96% of treatment-naive patients achieved SVR; and 93% of prior null responders achieved SVR. Comparable high response rates were obtained in the 12- or 24-week arms, supporting a 12-week treatment duration. Treatment was well tolerated. Four of 448 patients in the 8- and 12-week arms discontinued treatment because of adverse events. The most common adverse events were fatigue and headache.

Fig. 2. Aviator study. (A) Trial design [3]. This phase 2b study assesses the safety and efficacy of ABT-450/r (dosed 100/100mg to 200/100mg QD), ABT-267 (25mg QD), ABT-333 (400mg BID), and ribavirin in non-cirrhotic treatment-naïve patients and prior PegIFN/ribavirin null responders for 8, 12 or 24weeks. ABT-450, NS3 protease inhibitor, boosted with ritonavir (ABT-450/r); ABT-267, NS5A inhibitor; ABT-333, non-nucleoside NS5B polymerase inhibitor. (B) Results from the Aviator study [3]. SVR in treatment-naїve genotype 1 (GT1) patients and in GT1 null responder patients.

Discussion: what have we learned? 

First, for naive genotype 1 patients without cirrhosis («easy-to-cure patients»), this preliminary study suggests that the all-oral combination of 2 DAAs (ABT-450/r, ABT-333), and ribavirin for 12weeks is associated with a high SVR rate. According to subtype, no virologic failures occurred among the 26 genotype 1a naïve patients.

Second, this regimen (ABT-450/r, ABT-333, and ribavirin) is less effective in null or partial responders to previous therapy («difficult-to-cure patients»). Extending the treatment duration beyond 12weeks may not be an option since most of the virologic failures occurred during treatment. We do not really understand why treatments including DAAs are less effective in treatment-experienced patients when compared to naïve patients, even in the absence of IFN therapy. Innate immunity may still have a role in HCV clearance with these DAAs [5]. For previous non-responders, more potent combination with different compounds may be needed. The combination of several DAAs (ABT-450/r, ABT-267, ABT-333, and ribavirin) in non-cirrhotic prior null-responders provides excellent preliminary results. Moreover, PegIFN may remain an option in previous non-responders (or as a rescue therapy), since a high SVR rate was achieved when two DAAs were combined with PegIFN/ribavirin [6].

Third, we will have to wait for more data, with a larger number of patients, including difficult-to-cure patients with cirrhosis and previous non-response. Of course, phase 3 studies will provide more information about safety, effectiveness, and drug-drug interactions, especially when several new drugs are developed in the same regimen (and ABT-450 is boosted with ritonavir).

Conclusions

Finally, ABT-450-based regimen showed impressive results. It is unclear whether ribavirin will remain an important agent. For easy-to-cure patients, “genotype 1b with mild disease”, ribavirin may be not useful. For difficult-to-cure patients, “cirrhosis with prior non-response”, an intensive regimen may be necessary.

The phase 3 program is ongoing. The DAAs in the studies include ABT-450/r (protease inhibitor and ritonavir), ABT-267 (NS5A inhibitor) and ABT-333 (non-nucleoside polymerase inhibitor). Treatment duration will be 12weeks in non-cirrhotic patients and 12 or 24weeks in cirrhotic patients. All patients will be followed for 48weeks post-treatment. Co-formulated tablets of ABT-450/r and ABT-267 will be used in phase 3 trials. (http://www.clinicaltrials.gov.)

There is a realistic hope for an oral regimen against HCV since several DAA combinations have reported interesting preliminary results (increased SVR, low resistance and a preliminary good safety profile) [7], [8], [9]. We have to take into account this important revolution, but remain cautious and await larger phase 3 data, especially regarding safety and drug-drug interactions. Finally, we wish a nice flight to Aviator, and we hope that in the near future an IFN-free regimen will be available for patients with HCV infection.

Conflict of interest 

Tarik Asselah is a speaker and investigator for BMS, Boehringer-Ingelheim, Tibotec, Janssen, Gilead, Roche, and Merck.

References 

Source

Slow regression of liver fibrosis presumed by repeated biomarkers after virological cure in patients with chronic hepatitis C

Journal of Hepatology
Volume 59, Issue 4 , Pages 675-683, October 2013

Thierry Poynard, Joseph Moussalli, Mona Munteanu, Dominique Thabut, Pascal Lebray, Marika Rudler, Yen Ngo, Vincent Thibault, Helmi Mkada, Frederic Charlotte, Françoise Imbert Bismut, Olivier Deckmyn, Yves Benhamou, Marc Antoine Valantin, Vlad Ratziu, Christine Katlama, FibroFrance-GHPS group

Received 31 March 2013; received in revised form 29 April 2013; accepted 8 May 2013. published online 28 May 2013.

Abstract

Background & Aims

Chronic hepatitis C is both a virologic and fibrotic disease and complications can occur in patients with sustained virologic response (SVR) with residual fibrosis. Due to the limitations of repeated biopsies, no studies have assessed the dynamic of fibrosis before and after treatment. Using biopsy as reference, FibroTest™ has been validated as a biomarker of fibrosis progression and regression, with similar prognostic values. The aim was to estimate the impact of SVR on the dynamic of fibrosis presumed by FibroTest™.

Methods

In a prospective cohort, the main end point was the 10-year regression rate of fibrosis, defined as a minimum 0.20 decrease in FibroTest™, equivalent to one METAVIR stage.

Results

A total of 933 patients with both repeated FibroTest™ and transient elastography were included. At 10years, among the 415 patients with baseline advanced fibrosis, 49% (95% CI 33–64%) of the 108 SVR had a regression, which was greater than in the 219 non-responders [23% (14–33%; p<0.001 vs. SVR)] and not lower than in the 88 non-treated [45% (10–80%; p=0.39 vs. SVR)] patients. In all 171 SVR, cirrhosis regressed in 24/43 patients, but 15 new cirrhosis cases occurred out of 128 patients, that is only a net reduction of 5.3% [(24–15)=9/171); (2.4–9.8%)]. Four cases of primary liver cancer occurred in SVR [4.6% (0–9.8)], and 13 in non-responders [5.6% (1.5–9.8); p=0.07].

Conclusions

In patients with chronic hepatitis C, and as presumed by FibroTest™, virological cure was associated with slow regression of fibrosis 10years later, a disappointing 5% decrease in cirrhosis cases, and a remaining 5% risk of primary liver cancer.

Keywords: Cirrhosis, FibroTest™, FibroSure, Elastography

PII: S0168-8278(13)00345-0

doi:10.1016/j.jhep.2013.05.015

© 2013 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.

Source

SVR Tied to Lower Progression, Mortality in HIV/HCV+ With Moderate Fibrosis - the importance of treating coinfected patients

Provided by NATAP

53rd ICAAC Interscience Conference on
Antimicrobial Agents and Chemotherapy
September 10-13, 2013, Denver CO

53rd ICAAC, September 10-13, 2013, Denver

from Jules: SVR reduced risk for AIDS progression and serious liver-related events in non-advanced as well as in patients with advanced HCV disease, thus as the authors say all HIV+ patients should be treated for HCV quick without undue delay, delaying therapy risks progression of HIV & HCV, even for patients with non-advanced disease but of course mores for patients with advanced disease. With the expected availability of new HCV therapies later this year but with peg interferon, and in 2014 IFN-free regimens with 95-100% SVR rates in phase 2 are expected to become available, coinfected patients should be treated without undue delay. If you view the slides below on "Rates of Events" you will see progression to AIDS, liver decompensation, HCC, overall mortality & liver-related mortality is reduced by as much as 10-fold.

Mark Mascolini

Sustained virologic response (SVR) to interferon plus ribavirin (IFN/RBV) with nonadvanced or moderate fibrosis lowered the risk of mortality and liver-related progression in a large Spanish cohort of people with HIV/HCV coinfection [1]. The benefit was most pronounced in people with moderate (METAVIR F2) liver fibrosis.

Previous work established the benefits of eradicating HCV in people with advanced fibrosis or cirrhosis. But researchers working with the GESIDA 3606 Study Cohort observed that the clinical benefits of attaining SVR have not been established in people with less advanced fibrosis. They argued that this question is especially relevant for HIV/HCV-coinfected people. The GESIDA team conducted this retrospective analysis to assess the impact of IFN/RBV-induced SVR on mortality, liver-related events, and HIV progression in HIV/HCV-coinfected people with biopsy-proved nonadvanced liver fibrosis.

The study group consists of people with HIV and HCV who began IFN/RBV between January 2000 and January 2008 at 19 clinical centers across Spain. Baseline liver biopsies in all participants had a METAVIR score of F0, F1, or F2. Follow-up continued from the time IFN/RBV stopped until the last study visit, a second course of IFN/RBV, or death.

Among 695 people who met those criteria, 77 (11%) had a METAVIR score of F0, 290 (42%) had F1 fibrosis, 328 (47%) had F2 fibrosis, and 274 (39%) achieved SVR. Most people in the SVR and no-SVR groups (69% and 75%) were men, while CD4 counts averaged 562 and 536. The groups were similar in median age (39.8) and weight (68 kg), proportion with low educational level (62%), proportion of prior injection drug users (83%), and proportion with an undetectable HIV load (66%). The proportion of people with CDC category C disease was lower in the SVR group than in the no-SVR group (16% versus 22%, P < 0.05).

People who attained SVR included a lower proportion with HCV genotype 1 or 4 (44% versus 76%, P < 0.05) and thus a higher proportion with genotype 2 or 3 (56% versus 24%). The SVR group also included a lower proportion with a pretreatment HCV load at or above 500,000 IU/mL (62% versus 76%, P < 0.05) and a lower proportion who drank more than 50 g of alcohol daily (2% versus 6%, P < 0.05). METAVIR fibrosis scores did not differ significantly between people who attained SVR and those who did not.

Three variables predicted SVR: HCV genotype 2 or 3 (odds ratio [OR] 4.24, 95% confidence interval [CI] 2.91 to 6.19), pretreatment HCV load below 500,000 IU/mL (OR 1.88, 95% CI 1.27 to 2.78), and drinking less than 50 g of alcohol daily (OR 4.04, 95% CI 1.11 to 14.8).
Through 96 months of follow-up, cohort members who attained SVR had significantly lower Kaplan-Meier-estimated overall mortality (P = 0.010), liver-related mortality (P = 0.024), liver decompensation (P = 0.010), and liver-related events (which included liver-related death, liver decompensation, hepatocellular carcinoma, and liver transplantation) (P < 0.001).

Among people with an F2 METAVIR score, people who achieved SVR had significantly lower mortality (0.29 versus 1.07 per 100 person-year [py]), liver-related mortality (0.07 versus 0.53 per 100 py), AIDS incidence (0.14 versus 0.69 per 100 py), and liver decompensation rate (0.22 versus 1.31 per 100 py) (P < 0.05 for all differences) than people who did not attain SVR. An analysis focused on people with F2 fibrosis found that those attaining SVR had significantly lower mortality (0.16 versus 1.57 per 100 py), liver-related mortality (0.16 versus 1.05 per 100 py), and liver decompensation rate (0.16 versus 1.85 per 100 py) (P < 0.05 for all differences) than people who did not attain SVR. Among people with a METAVIR score of F0 or F1, these progression rates did not differ significantly between those who attained SVR and those who did not.

Cox regression analysis to determine risk of liver-related events according to METAVIR fibrosis stage adjusted for age, gender, history of injection drug use, CDC clinical category, CD4 count, HCV genotype, and HCV load. In this analysis people who attained SVR with F0 to F2 fibrosis or with F2 fibrosis had almost a 90% lower risk of progression, as indicated in the following list. The group with F0 or F1 fibrosis had about an 80% lower risk of progression, but this difference stopped short of statistical significance:

Progression risk with SVR versus no SVR:
METAVIR F0-F2: adjusted hazard ratio (aHR) 0.13, 95% CI 0.03 to 0.59, P = 0.008
METAVIR F2: aHR 0.11, 95% CI 0.01 to 0.86, P = 0.035
METAVIR F0-F1: aHR 0.21, 95% CI 0.02 to 1.94, P = 0.169

The GESIDA team concluded that "eradication of HCV in HIV/HCV-coinfected patients with nonadvanced liver fibrosis (F0 to F2), and, more specifically, with moderate stages of liver fibrosis (F2), is associated with a reduction in the risk of mortality and liver-related events." They argued that these findings "constitute a strong rationale for considering anti-HCV treatment in this population group, particularly treatment based on the newer and more effective direct antiviral agents."

ReferenceL

1. Berenguer J, Zamora FX, Díez C, et al. Hepatitis C eradication reduces liver decompensation, HIV progression, and death in HIV/HCV-coinfected patients with non-advanced liver fibrosis. 53rd ICAAC. September 10-13, 2013. Denver. Abstract H-1527.

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Hepatitis C Eradication Reduces Liver Decompensation, HIV progression, and Death in HIV/HCV-coinfected Patients with non-Advanced Liver Fibrosis

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