July 2, 2010

30 Jun 2010

A 5-month-old New York infant received a lifesaving liver transplant for advanced liver failure diagnosed following her birth 10 weeks premature. One of the smallest babies ever to successfully receive a liver transplant, she weighed 4 pounds at the time of the surgery.

The surgery was performed in February and was led by Dr. Tomoaki Kato, surgical director of liver and intestine transplant programs at NewYork-Presbyterian Hospital/Columbia University Medical Center, and chief of abdominal organ transplantation and professor of surgery at Columbia University College of Physicians and Surgeons.

"Performing a transplant in a premature infant this size is a major challenge where any technical issue would have been fatal, but it was the only option," says Dr. Kato. "Most babies born with her condition would not have the chance to grow up. This surgery shows that transplantation is possible -- although only at an academic medical center with appropriate resources and only with focused teamwork and dedication."

In the weeks after being born on Dec. 3, the patient was referred to NewYork-Presbyterian/Morgan Stanley Children's Hospital where she was diagnosed with an irreversible liver injury of unknown origin. Cared for in the neonatal intensive care unit, she was on a ventilator and had dangerous fluid buildup in her abdomen and difficulty feeding. After being on the organ waitlist for two weeks, a replacement liver became available in Florida.

"The donor organ wasn't a matching blood type and it was substantially larger than her diseased organ, but it was critical that we proceed. To accommodate its size we created an artificial abdominal wall using a Gore-Tex mesh," explains Dr. Kato. "Unlike other organs, the liver has the unique ability to adapt itself to the patient's body. In this case the organ is making itself smaller. As she grows, her new liver will grow with her."

In the weeks following the surgery, the patient started recognizing her mother and responding to her by smiling. The child has also gained the ability to get nutrition through a feeding tube rather than intravenously. Her liver function normalized, and soon after the Gore-Tex mesh was removed and her abdomen closed.

Her medical care has been overseen by Dr. Steven Lobritto, medical director of pediatric liver transplantation at NewYork-Presbyterian/Morgan Stanley Children's Hospital and associate clinical professor of pediatrics and medicine at Columbia University College of Physicians and Surgeons.

"While she is on immunosuppressant medication and received a blood-type mismatched organ, rejection is usually not a major issue in babies, whose bodies can more easily accept an organ than someone who is full grown," says Dr. Lobritto.

Collaboration With the Neonatal Intensive Care Unit

According to Drs. Kato and Lobritto, the success of this transplant was a direct result of a novel transplant collaboration with the neonatal intensive care unit.

The patient's tiny size and medical issues related to prematurity meant that she may not have received optimal treatment in the pediatric intensive care unit, where childhood transplant patients are normally treated. "Accommodating the patient in a NICU setting required thorough on-the-spot training for clinicians and caregivers at every level," says Dr. Lobritto.

Dr. Ulana Sanocka, the neonatologist in charge of caring for this transplanted child at NewYork-Presbyterian/Morgan Stanley Children's Hospital and an associate clinical professor of pediatrics at Columbia University College of Physicians and Surgeons, says: "It was a very rewarding collaborative experience. Everyone worked around the clock to ensure she received the best care possible."

Special Note to the Media: NewYork-Presbyterian physicians and surgeons are available for interviews about the surgical procedure. At the parents' request, the patient is not available for media interviews.

Organ Transplantation at NewYork-Presbyterian Hospital

The organ transplantation program at NewYork-Presbyterian Hospital -- which includes NewYork-Presbyterian Hospital/Weill Cornell, NewYork-Presbyterian Hospital/Columbia and The Rogosin Institute -- is the most active program of its kind in the nation, offering comprehensive and personalized care for the heart, liver, pancreas, kidney and lung. With outcomes ranked among the nation's best, the Hospital is dedicated to improving quality of life for its patients. NewYork-Presbyterian's dedicated teams of surgeons and physicians are responsible for many significant advances made over the past several decades in transplant surgery and the maintenance of healthy organs. The Hospital has been on the forefront of developing and improving anti-rejection medications (immunosuppressants), minimally invasive surgery for living donors, genetic methods to detect transplant rejection, strategies to increase opportunities for donor matching, islet cell transplantation, and the FDA-approved Left Ventricle Assist Device (LVAD) that functions as a bridge to transplantation for those waiting for a new heart.

NewYork-Presbyterian/Morgan Stanley Children's Hospital

NewYork-Presbyterian/Morgan Stanley Children's Hospital, located in New York City, offers the best available care in every area of pediatrics -- including the most complex neonatal and critical care, and all areas of pediatric subspecialties -- in a family-friendly and technologically advanced setting. Building a reputation for more than a century as one of the nation's premier children's hospitals, Morgan Stanley Children's Hospital is affiliated with the Department of Pediatrics at Columbia University College of Physicians and Surgeons, and is Manhattan's only hospital dedicated solely to the care of children and one of the largest providers of children's health services in the tri-state area with a long-standing commitment to its community. It is also a major international referral center, meeting the special needs of children from infancy through adolescence worldwide. NewYork-Presbyterian Hospital also comprises NewYork-Presbyterian Hospital/Columbia University Medical Center, NewYork-Presbyterian Hospital/Weill Cornell Medical Center, NewYork-Presbyterian Hospital/Westchester Division and NewYork-Presbyterian/The Allen Hospital. NewYork-Presbyterian is the #1 hospital in the New York metropolitan area and is consistently ranked among the best academic medical institutions in the nation, according to U.S.News & World Report.

Source: NewYork-Presbyterian Hospital
Article URL: http://www.medicalnewstoday.com/articles/193333.php

Four Rules to Help HCV Sufferers Sleep Well

July 1, 2010

By making sure these four rules are practiced daily, those with Hepatitis C will benefit from the resulting improvement in their sleep.

by Nicole Cutler, L.Ac.

An estimated three quarters of those with Hepatitis C wage an ongoing battle against chronic fatigue. Although it seems ridiculously simple, getting a deep, restful, complete night's sleep is one of the most effective solutions for this fatigue. Unfortunately, obtaining said sleep is not always an easy feat.

For those with Hepatitis C, sleep disturbances typically accompany their illness. In the January 2010 Journal of Clinical Gastroenterology, S. Sockalingam and colleagues presented a review of sleep disturbances in people with Hepatitis C. They reported that up to 60 percent of patients with chronic Hepatitis C experience sleep problems. Some of the proposed mechanisms responsible for sleeping troubles in those with Hepatitis C, include:

· Depression - Troubled sleep is considered by experts to be a hallmark sign of depression. It is estimated that between 24 and 70 percent of those with chronic Hepatitis C experience a major depressive disorder.

· Side effect of interferon/ribavirin treatment - Up to 30 percent of interferon-treated Hepatitis C patients has newly diagnosed sleep disturbances.

· Cirrhosis - For those with an advanced case of Hepatitis C, cirrhosis typically interferes with the sleep-wake cycle.

Sleep's Importance

Variations on sleeplessness include problems falling asleep, maintaining sleep or experiencing non-restorative sleep. Because sleep rejuvenates the psyche and immune system, sleeplessness affects energy level, mood and overall health. The result of poor sleep is fatigue, which always perpetuates chronic illness. Long-term sleep deprivation is practically guaranteed to worsen the severity of chronic Hepatitis C.

A good night's sleep is more important to the immune system's response to Hepatitis C than most people realize. The immune system is activated during the deepest stage of sleep to fight disease. This is why people tend to sleep longer when they're sick. Loss of sleep, even for a few short hours during the night, can prompt one's immune system to turn against healthy tissue and organs.

As published in a September 2008 issue of Biological Psychiatry, California researchers reported that losing sleep for even part of one night could trigger the key cellular pathway that produces tissue-damaging inflammation. Obviously, inviting such inflammation in the face of the Hepatitis C virus is a surefire way to fan the flames of liver damage.

Four Sleep Tips

Those with Hepatitis C need deep, restful sleep to maintain their health. Thus, the following tips should be regarded as a strict set of rules - rather than just mere suggestions:

1. Coffee Cut-Off - While several studies have demonstrated coffee's benefits to people with Hepatitis C, it should not be consumed after 4pm; restricting caffeine intake to the morning hours is even better. Even if you can fall asleep easily after an evening espresso, your body will not get the same kind of deep, restful sleep with caffeine circulating in your system.

2. Take Control of Your Sleep/Wake Cycle - You don't need to be an infant to benefit from an established bedtime. A stringent routine of retiring and rising at the same time every day can influence the body's sleep hormones to normalize.

3. Modify Your Environment - Coinciding with the absence of activity and light, people naturally sleep at nighttime. Because we are designed to slumber during the darkest, quietest part of the day, our sleep environment should reflect that, with sounds minimized, lights low and the television (and other illuminated and noisy electronics) turned off.

4. Relax Before Bed - It's hard to fall asleep when your mind and body are racing from an active day. Take some time to unwind before your allocated bedtime by purposefully relaxing. Some ways to do this could be meditating, taking a warm bath, drinking some herbal tea or doing some deep abdominal breathing.

While severe and/or recurring insomnia certainly warrants getting help from a physician, many people's sleep problems can be corrected by heeding the four rules described above. Individuals with Hepatitis C are especially prone to sleeping difficulties. Not surprisingly, those with this liver disease have a lot to gain from a good night's rest. Thus, cutting off coffee early in the day, setting a sleep/wake cycle, controlling the sleep environment and relaxing before bed should be considered standard practices for living healthfully with Hepatitis C.

References:

http://www.hcvadvocate.org/news/newsRev/2010/HJR-7.1.html#5, HCV and Sleep Disorders, Retrieved January 26, 2010, Hepatitis C Support Project, 2010.

http://www.hepatitis-central.com/mt/archives/2009/01/why_depression.html, Why Depression is Likely With Hepatitis C, Nicole Cutler, L.Ac., Retrieved January 29, 2010, Natural Wellness, 2010.

http://www.hepatitis-central.com/mt/archives/2009/07/back_to_basics.html, Back to Basics: Helping Your Body Fight Hepatitis C, Nicole Cutler, L.Ac., Retrieved January 29, 2010, Natural Wellness, 2010.

http://www.huffingtonpost.com/dr-michael-j-breus/sleep-hygiene-101-how-to_b_412965.html, Sleep Hygiene 101: How to Ensure a Better Night's Rest, Dr. Michael J. Breus, HuffingtonPost.com, Inc., 2010.

http://www.liverdisease.com/fatigue_hepatitis.html, Fatigue and Liver Disease/Hepatitis, Retrieved January 26, 2010, Melissa Palmer, MD, 2010.

http://www.ncbi.nlm.nih.gov/pubmed/19730115?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=2, A review of sleep disturbance in hepatitis C, Sockalingam S, et al, Retrieved January 26, 2010, Journal of Clinical Gastroenterology, January 2010.

http://www.psychologytoday.com/articles/200307/bedfellows-insomnia-and-depression, Bedfellows: Insomnia and Depression, Hara Estroff Marano, Retrieved January 29, 2010, Psychology Today, July 2003.

http://www.webmd.com/hepatitis/hepc-guide/managing-hepatitis-c , Managing Hepatitis C, Retrieved January 26, 2010, WebMD, LLC, 2010.

Source
Nature Reviews Drug Discovery 9, 501-503 (July 2010) doi:10.1038/nrd3214

Alisa Opar

Data from a late-stage trial of the most advanced of a new class of drugs targeting the hepatitis C virus protease fuel hopes for major improvements in treatment outcomes.

In May this year, Vertex Pharmaceuticals announced the first set of highly anticipated data from Phase III trials of telaprevir, which is competing to be the first protease inhibitor for the treatment of hepatitis C virus (HCV) infection to reach the market. The findings did not disappoint: telaprevir in addition to the current standard therapy was shown to be considerably more efficacious than the standard therapy alone.

Merck is hot on Vertex's heels with its drug boceprevir, which, like telaprevir, targets the key role of the HCV protease in the viral life cycle. Merck plans to release Phase III data for boceprevir later this year and Vertex expects results from two additional Phase III trials of telaprevir in the third quarter. If all goes well, both companies could file for regulatory approval this year and launch their drugs in 2011.

Protease inhibitors could represent a “revolution” in HCV treatment, says Stefan Zeuzem, Professor and Chief of Medicine at the J. W. Goethe University Hospital in Frankfurt, Germany. “The addition of a protease inhibitor to standard therapy is a milestone,” he says. “It's increased the cure rate by more than 30%. That is almost unprecedented within internal medicine. It is really, really rare that you have these breakthroughs.”

"The addition of a protease inhibitor to standard therapy is a milestone."

One of the biggest challenges in HCV treatment is that only about half of the patients with the genotype 1 strain of the virus — HCV1, the most common form in the United States and in Europe, and typically considered the most difficult to treat — obtain a sustained viral response (SVR), or cure, after completing standard therapy. Current treatment is a 48-week course of injections of pegylated interferon combined with the generic antiviral pill ribavirin. The arduous side effects of interferon, which include anaemia, depression and flu-like symptoms, lead many patients to curtail their treatment. Experts are hoping that protease inhibitors and other novel agents in the pipeline (Table 1) will shorten treatment duration, have better tolerability and cure more people.

Table 1 Selected drugs in Phase II or III trials for the treatment of HCV*
 
In Vertex's recently reported Phase III study, known as ADVANCE, 75% of patients infected with HCV1 who had not been previously treated achieved an SVR after receiving 12 weeks of telaprevir, pegylated interferon and ribavirin, followed by a course of standard therapy for at least another 12 weeks. The ADVANCE trial was response-guided, meaning that if in the telaprevir group the virus was sufficiently suppressed after 4 weeks, patients received only 24 weeks of total treatment — half the standard treatment time. Notably, about 70% of those who achieved SVR only received 24 weeks of therapy. Patients in the control group underwent standard therapy for 48 weeks and 44% achieved an SVR.
 
Both telaprevir and boceprevir might halve treatment duration to 24 weeks, although telaprevir might have an edge over boceprevir as its side effects seem to be milder; telaprevir causes rash and increases anaemia, but not to the same extent as boceprevir. The picture will be clearer later this year after Vertex and Merck report results of Phase III studies for treatment-experienced and treatment-naive patients with HCV1.

In addition to offering patients who have failed standard therapy another option, better drugs for HCV could spur more people to seek treatment. In fact, because the novel therapies seem so promising, a growing number of patients are delaying treatment until they become available. This phenomenon, called warehousing, is widespread, says Ira Jacobson, Chief of the Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, USA, and an investigator for the ADVANCE trial. For many people, waiting a year or so to start therapy makes sense because the illness progresses slowly, scarring the liver over years or even decades and eventually leading to cirrhosis, liver cancer or other conditions. “The idea is, why take therapy now if you have a 40–45% chance of success when you can wait and have something that might confer a 70% chance of success perhaps with the added advantage of shorter duration of therapy, as suggested by clinical trial data so far,” Jacobson explains.

Initially, telaprevir and boceprevir would be used in combination with interferon and ribavirin, but experts hope that new drugs will ultimately remove the need for interferon. However, it is unlikely that a protease inhibitor will be used alone because of problems with resistance. “The first monotherapy studies with telaprevir have shown that resistance develops within the first 2 weeks. The data have also shown that the [viral] mutants exist before treatment,” says Michael Manns, Head of the Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany. “As resistance is a problem, the FDA has restricted the use of monotherapy to 3 days in early studies, and then interferon plus ribavirin has to be added because the mutants for the protease are sensitive to interferon.”

To combat resistance, researchers are looking at using combinations of direct-acting antivirals. “This approach has been very successful at preventing resistance in HIV treatment,” says Robert Kauffman, Vertex's Chief Medical Officer. “If you have two drugs against two different viral targets for which there is no cross-resistance, to get a resistant variant, resistance needs to develop to both drugs, which is obviously much less likely than with just one drug.” Still, whether interferon-free regimens are possible, and, if they are, what will be the best combinations of direct-acting antivirals are “open questions,” says Manns.

Several companies are already tackling these questions. In addition to boceprevir and telaprevir, which are taken orally three times a day, second-generation protease inhibitors taken once a day are in Phase II trials (Table 1). “The big advantage we are hoping for from the second-wave protease inhibitors are improvements in the pharmacokinetic profile, dosing intervals, and perhaps some advances with respect to safety and tolerability,” says Zeuzem.

Although protease inhibitors are expected to reach the market first, investigational agents that block other HCV enzymes, such as non-nucleoside and nucleoside polymerase inhibitors, are also in development (Table 1). “Nucleoside polymerase inhibitors in particular appear to have a high genetic barrier to resistance, but the non-nucleosides also offer great promise in combination with other drugs,” says Jacobson. NS5A inhibitors are another novel class of agents that block a protein critical to viral replication; there is a “great deal of focus” on these compounds, Jacobson adds, because they show marked antiviral activity. In addition, trials of immunological therapies, new formulations of interferon, and antagonists to cyclophilins, which are human proteins used by the virus to augment its own replication, are all underway.

As yet, nobody knows what the most effective strategy might be. “We are now entering a phase where we have a large number of companies combining direct-acting antiviral drugs together, which have non-cross resistance patterns — a protease inhibitor with a NS5A inhibitor, a protease inhibitor with a non-nucleoside polymerase inhibitor, a protease inhibitor with a nucleoside inhibitor,” says Zeuzem. One of the key challenges in the clinical trials of such agents will be learning how to manage resistance and side effects related to the direct-acting antivirals, says Kaufmann, noting that these challenges will be compounded when the agents are combined.

“I think it will be a potentially breathtaking event when any of those trials gives us proof of concept that you can induce a sustained virologic response with combinations of pure antiviral drugs in the absence of interferon,” says Jacobson. “If such proof of concept materializes soon, I think it will further accelerate the development of interferon-free regimens.”

http://www.nature.com/nrd/journal/v9/n7/full/nrd3214.html
Liver Transpl. 2010 Jul;16(7):864-9.

Moon JI, Kwon CH, Joh JW, Jung GO, Choi GS, Park JB, Kim JM, Shin M, Kim SJ, Lee SK.
Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Abstract

The problem of graft size is one of the critical factors limiting the expansion of adult-to-adult living donor liver transplantation (LDLT). We compared the outcome of LDLT recipients who received grafts with a graft-to-recipient weight ratio (GRWR) < 0.8% or a GRWR >/= 0.8%, and we analyzed the risk factors affecting graft survival after small-for-size grafts (SFSGs) were used. Between June 1997 and April 2008, 427 patients underwent LDLT with right lobe grafts at the Department of Surgery of Samsung Medical Center. Recipients were divided into 2 groups: group A with a GRWR < 0.8% (n = 35) and group B with a GRWR >/= 0.8% (n = 392). We retrospectively evaluated the recipient factors, donor factors, and operative factors through the medical records. Small-for-size dysfunction (SFSD) occurred in 2 of 35 patients (5.7%) in group A and in 14 of 392 patients (3.6%) in group B (P = 0.368). Graft survival rates at 1, 3, and 5 years were not different between the 2 groups (87.8%, 83.4%, and 74.1% versus 90.7%, 84.5%, and 79.4%, P = 0.852). However, when we analyzed risk factors within group A, donor age and middle hepatic vein tributary drainage were significant risk factors for graft survival according to univariate analysis (P = 0.042 and P = 0.038, respectively). Donor age was the only significant risk factor for poor graft survival according to multivariate analysis. The graft survival rates of recipients without SFSD tended to be higher than those of recipients with SFSD (85.3% versus 50.0%, P = 0.074). The graft survival rates of recipients with grafts from donors < 44 years old were significantly higher than those of recipients with grafts from donors >/= 44 years old (92.2% versus 53.6%, P = 0.005). In conclusion, an SFSG (GRWR < 0.8%) can be used safely in adult-to-adult right lobe LDLT when a recipient is receiving the graft from a donor younger than 44 years. Liver Transpl 16:864-869, 2010. (c) 2010 AASLD.

PMID: 20583075 [PubMed - in process]

Source
Michael Carter, Friday, July 02, 2010

Insulin resistance is associated with an impaired response to hepatitis C therapy for HIV-positive patients, Spanish investigators report in the online edition of the Journal of Acquired Immune Deficiency Syndromes.

“Our findings suggest that insulin resistance is an important determinant of poor response to anti-HCV [hepatitis C virus] therapy in HIV/HCV-coinfected patients”, comment the authors.

Recommended treatment for hepatitis C consists of pegylated interferon and weight-dosed ribavirin. The aim of therapy is an undetectable hepatitis C viral load 24 weeks after the completion of treatment. This is called a sustained virological response.

However, many patients do not achieve this outcome, and a poorer response to hepatitis C therapy is seen in HIV/hepatitis C-co-infected individuals.

Others factors associated with a lower chance of achieving a sustained virological response include hepatitis C genotype, hepatitis C viral load, fibrosis stage, and age.

Some research has suggested that the presence of insulin resistance also impairs responses to hepatitis C therapy. To gain a clear understanding of this issue, investigators from the HIV outpatient clinic of the Gregorio Maranon Hospital in Madrid performed a retrospective analysis involving 134 patients treated for hepatitis C between 2000 and 2007.

For each patient an insulin resistance score was calculated using the homeostatic model assessment (HOMA) method. An insulin resistance score was obtained using the following formula: fasting plasma glucose was multiplied by fasting serum insulin and divided by 22.5. Insulin resistance was diagnosed when a patient had a score of 3.8 of higher.

Most of the patients (77%) were men, and the median age was 40 years. The majority of patients (67%) were infected with the harder to treated hepatitis C genotypes – 1 and 4. In the majority of cases (81%) hepatitis C therapy included pegylated interferon.

The median HOMA-insulin resistance score was 2.5, and 31% of patients were diagnosed with insulin resistance.

Baseline insulin resistance scores were significantly lower for patients who achieved a sustained response to hepatitis C therapy than those who did not (1.9 vs. 3.3, p = 0.005).

Statistical analysis showed that the factors associated with achieving a sustained response to treatment included infection with the easier-to-treat genotypes 2 and 3 (OR = 6.7; 95% CI, 2.71-16.98, p < 0.001), and the absence of insulin resistance (OR = 3.3; 95% CI, 1.36-9.26, p = 0.008).

These findings were unaltered when the investigators controlled for age, gender, body mass index, type of interferon used in therapy, and fibrosis stage.

Moreover, the investigators found that even after controlling for potentially confounding factors, the presence of insulin resistance was associated with a poorer virologic response to hepatitis C therapy at weeks 4, 12, 24, 48, and 72.

“HOMA-insulin resistance should be included in the routine baseline evaluation of HIV/HCV-coinfected patients who are candidates for treatment with interferon and ribavirin”, conclude the investigators.

Reference

Ryan P et al. Insulin resistance impairs response to interferon plus ribavirin in patients coinfected with HIV and hepatitis C virus. J Acquire
 
http://www.aidsmap.com/en/news/93CBEFCF-9B51-48FA-94E9-18A3EA3335B5.asp