November 24, 2011

Largest Ever Genetic Study of Liver Function Could Point the Way to New Treatments

Published: October 16, 2011. Imperial College London

Researchers have identified a large number of areas in the human genetic code that are involved in regulating the way in which the liver functions, in a new study of over 61,000 people, published today in the journal Nature Genetics.

The work is an international collaboration led by Imperial College London and it identifies 42 genetic regions associated with liver function, 32 of which had not been linked to liver function before. The work should lead to a better understanding of precisely what goes wrong when the liver ceases to work normally. Ultimately, it could point the way to new treatments that can improve the function of the liver and help to prevent liver damage.

The liver is the body's largest internal organ and the British Liver Trust estimates that around two million people in the UK have a liver problem at any one time. The liver carries out hundreds of different tasks, including making proteins and blood clotting factors, and helping with digestion and energy release. It also purifies the blood of bacteria, and of the by-products of digestion, alcohol and drugs.

In the new genome-wide association study, the researchers compared the genetic makeup of over 61,000 people, in order to identify areas of the genetic code that were associated with liver function.

The team assessed the function of the volunteers' livers by looking at the concentrations of liver enzymes in their blood. People who have liver damage have high concentrations of these enzymes, which are associated with an increased risk of conditions such as cirrhosis, type 2 diabetes and cardiovascular disease.

Dr John Chambers, the lead author of the study from the School of Public Health at Imperial College London, said: "The liver is a central hub in the body and because it has so many diverse functions, it is linked to a large number of conditions. Our new study is a big step towards understanding the role that different genes play in keeping the liver working normally, and towards identifying targets for drugs that can help prevent the liver from functioning abnormally or becoming susceptible to disease."

The researchers identified 42 areas on the genetic code associated with liver function and they then went on to pinpoint 69 associated genes within these areas. Some of the genes are known to play a part in other functions in the body, including inflammation and immunity, and metabolising glucose and carbohydrates.

Professor Jaspal S Kooner, the senior author of the study from the National Heart and Lung Institute at Imperial College London, said: "This massive international research effort provides in-depth new knowledge about the genes regulating the liver. We are particularly excited about the genes whose precise role we don't yet know. Investigating these further should help us to fill in the gaps in our understanding about what happens when the liver ceases to function normally and how we might be able to tackle this."

Professor Paul Elliott, also a senior author of the study, from the School of Public Health at Imperial College London, said: "Liver problems affect a huge number of people and they can have a devastating effect on a person's quality of life. This study represents a vast discovery that opens up multiple new avenues for research."


Predicting clinical outcomes using baseline and follow-up laboratory data from the hepatitis C long-term treatment against cirrhosis trial

HepatologyVolume 54, Issue 5, pages 1527–1537, November 2011

Marc G. Ghany1,*,§, Hae-Young Kim2, Anne Stoddard2, Elizabeth C. Wright3, Leonard B. Seeff4, Anna S.F. Lok5, the HALT-C Trial Group

Article first published online: 28 OCT 2011
DOI: 10.1002/hep.24550
Copyright © 2011 American Association for the Study of Liver Diseases


Predicting clinical outcomes in patients with chronic hepatitis C is challenging. We used the hepatitis C long-term treatment against cirrhosis (HALT-C) trial database to develop two models, using baseline values of routinely available laboratory tests together with changes in these values during follow-up to predict clinical decompensation and liver-related death/liver transplant in patients with advanced hepatitis C. Patients randomized to no treatment and who had ≥2-year follow-up without a clinical outcome were included in the analysis. Four variables (platelet count, aspartate aminotransferase [AST]/alanine aminotransferase [ALT] ratio, total bilirubin, and albumin) with three categories of change (stable, mild, or severe) over 2 years were analyzed. Cumulative incidence of clinical outcome was determined by Kaplan-Meier analysis and Cox regression was used to evaluate predictors of clinical outcome. In all, 470 patients with 60 events were used to develop models to predict clinical decompensation. Baseline values of all four variables were predictive of decompensation. There was a general trend of increasing outcomes with more marked worsening of laboratory values over 2 years, particularly for patients with abnormal baseline values. A model that included baseline platelet count, AST/ALT ratio, bilirubin, and severe worsening of platelet count, bilirubin, and albumin was the best predictor of clinical decompensation. A total of 483 patients with 79 events were used to evaluate predictors of liver-related death or liver transplant. A model that included baseline platelet count and albumin as well as severe worsening of AST/ALT ratio and albumin was the best predictor of liver-related outcomes. Conclusion: Both the baseline value and the rapidity in change of the value of routine laboratory variables were shown to be important in predicting clinical outcomes in patients with advanced chronic hepatitis C. (HEPATOLOGY 2011;)


Living with chronic illness during the holiday season

Posted on

In the U.S., we’re getting ready to celebrate Thanksgiving. Soon, people around the world will turn their attention to the holiday season. Chronic health problems can take a toll on relationships any time of the year. Most people have to experience unrelenting pain or illness themselves before they understand how debilitating it is, physically and mentally. Loved-ones (by whom I mean family and close friends) may be in some form of denial about what’s happened to you, or they may be scared and worried about the future. Bottom line, suffering from a chronic condition can be an ongoing crisis—for you and for those you’re close to.

That crisis can come to a head during the holidays when people’s expectations of one another are high and when stress levels for everyone are likely to be off the charts for any number of reasons—health, financial, relationship issues. If you’re like me, during the rest of the year, you carefully limit interactions with others in order to manage your symptoms; on a typical day, your most complex decision may be to choose between showering and shopping! But when the holidays arrive, you’re suddenly thrust into the middle of a lively and chaotic social scene where you’re expected to participate in a range of activities, often for days in a row. A bit of advance warning to loved-ones can go a long way toward minimizing stress levels over unrealistic expectations.

I know that this piece won’t apply to everyone. One of the heartbreaking consequences of living with chronic pain and illness is that some people are unable to be with loved-ones at all during the holidays, either because people are too disabled by their pain or illness to be able to gather with others, or because family and close friends having drifted out of their lives. I know the pain of that isolation; I’ll be writing about it in my next piece.

For those of you who are able to gather with others, the holidays can be a recipe for double disaster—the increase in activity exacerbates your physical symptoms, while coping with sadness, frustration, and maybe even guilt about your physical limitations gives rise to emotional pain. No wonder many people with health problems dread the approaching holidays.

If you’re one of the many people with chronic health problems who don’t look sick, the initiative is with you to make your condition visible. Here are some suggestions for helping loved-ones understand what your life is like and for giving them a heads-up on what to expect from you during the holidays.

Share information with them from the Internet or from books

Often the best way to educate loved-ones about chronic pain and illness is to use a neutral source because it takes the emotional impact out of the communication. A quick web search will yield a host of organizations devoted to every conceivable medical problem. Print out select pages or forward a few links to family and close friends. Alternatively, if you have a book about your condition, photocopy the pages that cover what you’d like them to know about you. In your accompanying note, keep it “light”—you could joke that “there won’t be a test.” But also make it clear that this favor you’re asking is important to you.

Write a letter

Many years ago, two friends of mine were in couples therapy. They weren’t able to speak to each other about their marital problems without one of them shutting down emotionally and the other reacting by shouting recriminations. Their therapist told them to write letters to each other expressing their feelings and their concerns about the marriage. It turned out to be a major first step in healing their relationship.

If you decide to write a letter, be sure it’s not accusatory. In composing it, use the word “I” more than the word “you.” Without complaining, express how difficult it’s been for you to adjust to this unexpected change in your life and how you wish you could be as active as you once were during the holidays.

You could briefly describe what your day-to-day life is like, including how unpredictable your condition is which means that you can’t know for sure how you’ll feel on the day of the actual gathering no matter how much you rest in advance. (This is the hardest concept for most loved-ones to comprehend—that we can spend weeks before a big event in full “rest mode,” but still feel very sick when the day arrives.)

I would end by telling them what to expect from you during the holidays—that you may have to skip some events, that you may have to excuse yourself right after eating to go lie down, that you may have to come late and leave early. In my experience, spelling out my limitations ahead of time is helpful not just to others, but to me, because I find it much easier to exercise the self-discipline it takes to excuse myself from a room full of people if I know that at least some of them are already expecting it.

P.S. It will be tempting to send an email, and if you have a lot of people you want to communicate with, it may be the most feasible way to reach everyone. But one thing’s for sure: people will read a handwritten letter, antiquated document that it’s become!

Find that ONE ally and enlist his or her help

If you have just one close friend or family member who understands what you’re going through, enlist his or her help in explaining your condition and your limitations. Before the holidays start, you could ask your ally to talk to loved-ones on your behalf or to be present when you talk to them. Ask your ally to be supportive if you have to excuse yourself in the middle of a gathering, or even to let you know if you’re wilting (as we call it in my household). It’s so helpful for me to be “prompted” by my ally because, when I start to overdo things, adrenaline kicks in which fools me into thinking I’m doing fine. But using adrenaline to get by just sets me up for a bad crash later on.

Your ally may be a close friend or family member who’s just waiting for you to enlist his or her help. Think long and hard before you decide there’s no such person in your life.

In the end, you may have to recognize that some loved-ones may never accept your limitations

Some family and close friends may refuse to accept that you’re disabled by pain or illness. I know this from personal experience and it hurts. Try to recognize that this inability is about them, not you. Don’t let their doubt make you doubt yourself. Your medical condition may trigger their own fears about illness and mortality, or they may be so caught up in problems in their own lives that they’re not able to see their way clear to empathize with you.

Just as you can’t force people to love you, you can’t force people to accept you. But getting angry at them just exacerbates your own symptoms. That’s why it’s important to protect yourself from allowing their lack of understanding to continually upset you. Think of it as protecting yourself from another chronic condition: chronic anger.

The physical suffering that accompanies chronic pain and illness is hard enough to endure without adding emotional suffering to it. When I feel let down family or close friends, the first thing I do is acknowledge how much it hurts. Then I reflect on the many possible reasons for their behavior. Finally, I work on genuinely wishing them well. These three steps immediately lessen my emotional suffering.

As you experiment with these suggestions, treat yourself kindly. Don’t blame yourself if one of them doesn’t work out. Instead, give yourself credit for having had the courage to try! My heartfelt wish is that your loved-ones come to understand and accept your limitations, but that if they don’t, you’ll be able to accept them as they are without bitterness.

Toni Bernhard was a law professor at the University of California—Davis, serving six years as the law school’s dean of students. She is the author of How to Be Sick: A Buddhist-Inspired Guide for the Chronically Ill and Their Caregivers and can be found online at

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November 23, 2011

Are you ready for World AIDS Day, December 1?

November 23, 2011
By Miguel Gomez, Director

“Leading with Science. United for Action.” is the U.S. Government theme for World AIDS Day 2011. This year, we are thankful for scientific advances in the response to HIV/AIDS, leading Secretary Clinton to call for an “AIDS-free generation.” Creating an AIDS-free generation has never been a policy priority for the U.S. Government until now, because this goal would have been unimaginable just a few years ago. Secretary Clinton’s call echoes the historic charge of the National HIV/AIDS Strategy.

On December 1st, people all around the world will commemorate World AIDS Day. We will think about how far we have come in the last 30 years and we at want everyone to get involved.

What can you do?
  1. Watch and share Secretary Hillary Clinton’s historic speech on HIV/AIDS which calls for an “AIDS Free Generation.”
  2. Plan a community event and/or take a photo for Facing AIDS. Share your message of why we all need to step up and face AIDS together.
  3. Print posters and tools from our World AIDS Day resources and use them at your events. Many are customizable and in English and Spanish.
  4. Locate HIV testing and other HIV services: Use and share the HIV/AIDS Prevention & Service Providers Locator and add the widget to your website or blog.
  5. Learn about and share the National HIV/AIDS Strategy. Read about agencies who are putting the strategy in action and talk about it with your colleagues — what would it take to make the goals of the Strategy real in your community?
  6. Follow our blogs and tweets  from guest blogs from the CDC and other Federal partners.
  7. Use the hashtag #WAD11  when sharing your thoughts on Twitter or Facebook.
We are all united together to take at least one small action to commemorate World AIDS Day. What are you doing in your community?


Researchers determine how antibody recognizes key sugars on HIV surface

November 23, 2011

HIV is coated in sugars that usually hide the virus from the immune system. Newly published research reveals how one broadly neutralizing HIV antibody actually uses part of the sugary cloak to help bind to the virus. The antibody binding site, called the V1/V2 region, represents a suitable HIV vaccine target, according to the scientists who conducted the study. In addition, their research reveals the detailed structure of the V1/V2 region, the last part of the virus surface to be visualized at the atomic level.

The study was led by Peter D. Kwong, Ph.D., chief of the Section of the Vaccine Research Center at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.

Some people who have been infected with HIV for several years begin to make antibodies that can neutralize a wide range of . These broadly neutralizing antibodies bind to one of four sites on the virus. One site involves a sugar at a spot called amino acid residue 160. ( are the building blocks of proteins.) The sugar is located on the protein-based spikes that jut out of the surface of HIV.

The new study demonstrates how a broadly neutralizing called PG9 disarms the virus by grabbing hold of the sugar at residue 160, along with part of a second sugar and a short string of amino acid residues in the V1/V2 region of an HIV spike.

Similarly, a separate, recently published report* from the IAVI Neutralizing Antibody Center at The Scripps Research Institute showed how a different broadly neutralizing HIV antibody also binds to the virus via two sugars and a string of . Taken together, these two studies indicate that in some cases, the combination of viral sugars and amino acids can form the binding site for broadly neutralizing HIV antibodies.

The new study may also help scientists who are examining data from the clinical trial of the first HIV vaccine to demonstrate effectiveness in people (

Recent analyses of blood samples from that trial showed that study participants who were vaccinated and then developed antibodies to the V1/V2 region were less likely to become infected. Although the role of those antibodies in protection against HIV is unknown, this finding underscores how understanding antibody-V1/V2 binding could aid the design of a more effective .

More information: JS McLellan et al., Structure of HIV-1 gp120 V1V2 domain with broadly neutralizing antibody PG9. Nature DOI: 10.1038/nature10696 (2011).

*R Pejchal et al., A potent and broad neutralizing antibody recognizes and penetrates the HIV glycan shield. Science DOI: 10.1126/science.1213256 (2011).
Provided by National Institutes of Health


Video: Mount Sinai Medical Center Launches Initiative to Erase the Stigma of Hepatitis C


Along with shattering the stigma surrounding the Hepatitis C virus, Dr. Dieterich wants patients to understand that testing positive for the virus is not a death sentence if caught early.

Also See: The Mount Sinai Medical Center Launches Initiative to Erase the Stigma of Hepatitis C and Encourage Everyone to Get Tested

Acetaminophen: Repeated Use of Slightly Too Much Can Be Fatal

Laurie Barclay, MD

November 22, 2011 — Repeated doses of slightly too much acetaminophen (known as paracetamol in the United Kingdom and elsewhere in Europe) can be fatal, according to the results of a large, single-center cohort study published online November 22 in the British Journal of Clinical Pharmacology.

"On admission, these staggered overdose patients were more likely to have liver and brain problems, require kidney dialysis or help with breathing and were at a greater risk of dying than people who had taken single overdoses," senior author Kenneth J. Simpson, MBChB (Hons), MD, FRCP (Edin), from the University of Edinburgh and Scottish Liver Transplant Unit in the United Kingdom, said in a news release.

"They haven't taken the sort of single-moment, one-off massive overdoses taken by people who try to commit suicide, but over time the damage builds up, and the effect can be fatal," he adds.

In the United Kingdom, acetaminophen hepatotoxicity is the leading cause of acute liver failure (ALF). However, the effect of a staggered overdose pattern or delayed hospital presentation on mortality or need for emergency liver transplantation was previously unknown.

Of 663 patients admitted with acetaminophen-induced severe liver injury between 1992 and 2008, 161 (24.3%) had taken a staggered overdose. Compared with patients who took an overdose at a single time, patients with staggered overdose were significantly older and more likely to abuse alcohol.

When asked why they repeatedly ingested more than the recommended dose of acetaminophen, patients with staggered overdose most often cited pain relief as their rationale (58.2%).
Compared with patients who took an overdose at a single time, those who took staggered overdoses had lower total ingested doses and lower serum alanine aminotransferase (ALT) levels on admission. Nonetheless, they were more likely to be encephalopathic and to require renal replacement therapy or mechanical ventilation.

Although mortality was higher in staggered overdoses than in single-time overdoses (37.3% vs 27.8%; P = .025), the staggered overdose pattern was not an independent predictor of mortality. For staggered overdoses, sensitivity of the King's College poor prognostic criteria was reduced (77.6%; 95% confidence interval [CI], 70.8% - 81.5%).

Delayed presentation to medical services more than 24 hours after single-time overdose occurred in 44.9% of those in whom accurate timings could be determined, and was independently associated with death or liver transplantation (odds ratio [OR], 2.25; 95% CI, 1.23 - 4.12; P = .009).

In their logistic regression analysis, the investigators controlled for signs and symptoms, such as hepatic encephalopathy and prothrombin time, as well as various demographic factors.

"Staggered overdoses or patients presenting late after an overdose need to be closely monitored and considered for the paracetamol antidote, N-acetylcysteine [NAC], irrespective of the concentration of paracetamol in their blood," Dr. Simpson said.

Because both these groups are at increased risk of developing multiorgan failure, they should be considered for early transfer to specialist liver centers.

Limitations of this study include reliance on patient recall regarding the time of last ingestion, total paracetamol dose, and suicidal intent; limited data regarding the use of concomitant P450 enzyme inducers or recent fasting; and selection bias for the more severe cases of acetaminophen toxicity in Scotland.

"[T]his large cohort study demonstrates the deleterious effects of delayed presentation and staggered overdose pattern upon outcome following paracetamol-induced acute liver injury," the study authors conclude. "Both delayed presentation > 24 hours and staggered overdoses are strongly associated with multiorgan injury and the need for [liver transplantation]. Patients presenting with these overdose patterns should be treated as high risk for progression to ALF, and should receive NAC in their presenting hospital whilst awaiting serial ALT and PT levels."

This study received no external funding. The authors have disclosed no relevant financial relationships.

Br J Clin Pharmacol. Published online November 22, 2011.


New HCV Drugs at AASLD

62th Annual Meeting of the American
Association for the Study of Liver Diseases
San Francisco 2011 Nov 6-9

from Jules of NATAP: There were so many positive presentations on new HCV drugs in development that one can only conclude SVR/'cure rates' will eventually be 100% for all treatable patients, whether patients are white, black or gentotypes 1 or 2/3. The once-daily HCV nucleotide PSI-7977 captured the imagination at AASLD with studies in only 40 patients with genotype 2/3 showing 100% cure rates receiving interferon-free regimen of PSI-7977+ribavirin for only 12 weeks, in this study their are 4 different regimens studied, see the link below to read the entire details. In the genotype 1 study 95 patients received PSI-7977+peg/rbv for 12 weeks followed by 12 additional weeks of Peg/Rbv alone, with 91-98% SVR rates, there were no viral failures, 4 patients withdrew due to Peg/Rbv side effects. This drug is entering Phase 3 studies in the Spring 2012, the last phase before FDA approval, which could take until 2014. The manufacturer Pharmasset has a 2nd nucleotide PSI-938 in earlier development and has already conducted studies combining these 2, and will conduct further studies combining them. Two other major classes of drugs are in accelerated development. The potent once-daily BMS NS5A inhibitor BMS-790052 is moving quickly through development being studied currently in an interferon-free 2-drug combination in genotype 1 patients with PSI-7977, the study is ongoing and results are not ready yet. Several studies of BMS-790052 presented at AASLD are reported below. Currently in Phase 3 are 2 new HCV protease inhibitors Tibotec's once-daily TMC-435 and Boerhinger Ingelheim's once-daily BI-201355, both are potent, and study results for both drugs were presented at AASLD and are linked to below. Tibotec is also studying their protease TMC-435 in combination with PSI-7977. BI also reported study results at AASLD of their interferon-free regimen which includes their protease BI-201335 + their NNRTI BI-207127 and ribavirin, linked to below. Tibotec announced study results for the first time for a new NNRTI TMC-647055, results presented below. Roche reported study results for their potent HCV protease danoprevir, linked to below, and will present at EASL new results of low-dose ritonavir boosted danoprevir in the near future. Study results of a combination of the BMS NS5A + their HCV protease BMS-790032 was reported at AASLD, linked to below. The first-in-class cyclophillin inhibitor from Novartis potent alisporivir/DEB025 is currently in phase 3 development, study results in genotype 1 were reported last Spring at EASL and study results in genotype 2 were reported at AASLD, linked to below. Vertex reported study results of their potent QUAD therapy regimen which includes telaprevir+ their NNRTI VX-222 + Peg/Rbv, results reported below. Merck reported early study results from an 8-day monotherapy study of their potent 2nd generation HCV protease inhibitor MK-5172, which showed 5 to 5.5 log reductions, so far perhaps the most potent protease, and they presented a poster showing in vitro this protease is active against, it suppresses protease resistant viruses, suggesting patients who fail with resistance would benefit from this protease and it would also be a potent first-line protease for treatment-naive patients, these studies linked to below. Merck also reported their first study pre-clinical data for a new NS5A inhibitor MK-4882 they discovered & are developing, which appears potent showing 4-log viral load reductions in the chimp after, linked to below. GSK reported for the first time on their new potent NS5A inhibitor GSK-2336805 showing early results from a single and repeat dose study in patients, see link below to view results. Gilead is researching 2, 3 and 4 drug HCV regimens with and without interferon and without ribavirin, Gilead has drugs of their own in every class including protease, NNRTI, NS5A and nucleotide, and have studies exploring these regimens ongoing, with further results to be presented in the near future, they did present some preliminary study data at AASLD, linked to below, but the study results expected to be reported in the near future from these ongoing studies will be much more informative and are highly anticipated. Abbott as well is in the middle of conducting ongoing studies so they did not have any study results to report at AASLD, but they have a potent HCV protease, 2 NNRTIs, and other classes of drugs in development, so it is expected they will in the near future also be presenting highly anticipated results from these ongoing studies. Presidio, a small biotech, is developing a potent NS5A inhibitor PPI-461and reported results from their dose-ranging study at AASLD, linked to below. Achillion & Inhibitex, 2 small biotechs, reported very promising study data on their drugs, Achillion is developing a potent HCV protease and a promising 2nd generation NS5A inhibitor, expected to be active against, to suppress NS5A resistant virus, they reported interesting data at AASLD, linked to below. As well Inhibitex reported their first new data on a higher dose of their nucleotide INX-189 at AASLD, it looks potent, data linked to below. BMS reported study results for their new peg-lambda interferon showing it to be potent with much less side effects, linked to below. Roche is developing a nuke mericitabine, it is rather advanced stage of development, and they reported encouraging resistance data, linked to below. In sum, is there any doubt that we can eventually expect a 100% 'cure rate' in all patients who will be treatable.

AASLD: PROTON: PSI-7977 & Peg/RBV in Treatment-naïve Patients with HCV GT1: Sustained Virologic Response - (11/08/11)

AASLD: PSI-7977: ELECTRON Interferon is not required for Sustained Virologic Response in Treatment-Naïve Patients with HCV GT2 or GT3 - (11/07/11)

AASLD: High sustained virologic response (SVR24) rates with response-guided danoprevir (DNV; RG7227) plus PegIFN alfa-2a (40KD) and ribavirin (P/R) in treatment-naive HCV genotype 1 (G1) patients: results from the ATLAS study - (11/07/11)

AASLD: Treatment with the 2nd generation HCV protease inhibitor BI 201335 results in high and consistent SVR rates - results from SILEN-C1 in treatment-naïve patients across different baseline factors - (11/08/11)

AASLD: High SVR following IFN-free treatment of chronic HCV GT1 infection for 4 weeks with HCV protease inhibitor BI 201335, polymerase inhibitor BI 207127 and ribavirin, followed by BI 201335 and PegIFN/ribavirin - the SOUND-C1 study - (11/08/11)

AASLD: Virologic response to an interferon-free regimen of BI 201335 and BI 207127, with and without ribavirin, in treatment-naïve patients with chronic genotype-1 HCV infection: Week 12 interim results of the SOUND-C2 study - (11/08/11)

AASLD: SILEN-C3: treatment for 12 or 24 weeks with BI 201335 combined with peginterferon alfa-2a and ribavirin in treatment-naïve patients with chronic genotype-1 HCV infection - (11/07/11)

AASLD: Positive Interim Results from Interferon-Free Phase 2b SOUND-C2 Study with Boehringer Ingelheim's Two Investigational HCV Direct Acting Antivirals Presented at AASLD - press release - (11/08/11)

AASLD: Once-daily alisporivir interferon (IFN)-free regimens achieve high rates of early HCV clearance in previously untreated patients with HCV genotype (G) 2 or 3 - (11/09/11)

AASLD: Novartis DEB025 data showed viral clearance as early as six weeks and potential for interferon-free therapy in hepatitis C patients - (11/07/11)

AASLD: TMC435 in Combination with Peginterferon and Ribavirin in Treatment-naïve HCV Genotype 1 Patients: Final Analysis of the PILLAR Phase IIb Study (TMC435-C205) - (11/08/11)

AASLD: Human safety, pharmacokinetics and antiviral activity of TMC647055, a novel HCV non-nucleoside polymerase inhibitor - (11/07/11)

AASLD: QUAD VX-222/Telaprevir in Combination With Peginterferon-alfa-2a and Ribavirin in Treatment-naïve Genotype 1 HCV Patients Treated for 12 Weeks: ZENITH Study, SVR12 Interim Analysis - (11/09/11)

AASLD: Daclatasvir (DCV; BMS-790052), an NS5A Replication Complex Inhibitor, in Combination With Peginterferon Alfa-2b and Ribavirin in Japanese Treatment-Naïve and Nonresponder Patients With Chronic HCV Genotype 1 Infection - (11/10/11)

AASLD: Combination Therapy of Treatment-Naïve and Nonresponder Patients With HCV Genotype 1 Infection With Daclatasvir (DCV; BMS-790052), an NS5A Replication Complex Inhibitor, in Combination With Peginterferon Alfa-2a and Ribavirin - (11/10/1

AASLD: Dual Oral Combination Therapy with the NS5A Inhibitor Daclatasvir(DCV; BMS-790052) and the NS3 Protease Inhibitor Asunaprevir(ASV; BMS-650032) Achieved 90% Sustained Virologic Response (SVR12) in Japanese HCV Genotype 1b-Infected Null Responders - (11/08/11)

AASLD: Evaluation of Drug Interaction Potential of the HCV Protease Inhibitor Asunaprevir (ASV; BMS-650032) at 200 mg Twice Daily (BID) in Metabolic Cocktail and P-glycoprotein (P-gp) Probe Studies in Healthy Volunteers - (11/16/11)

AASLD: Single-Dose Pharmacokinetics of Daclatasvir (DCV; BMS-790052) in Subjects With Hepatic Impairment Compared With Healthy Subjects - (11/16/11)

AASLD: Daclatasvir (DCV; BMS-790052) Has No Clinically Significant Effect on the Pharmacokinetics of a Combined Oral Contraceptive Containing Ethinyl Estradiol and Norgestimate in Healthy Female Subjects - (11/16/11)

AASLD: GSK2336805 HCV NS5A Inhibitor Demonstrates Potent Antiviral Activity in Chronic Hepatitis C (CHC) Genotype 1 Infection: Results from a First Time in Human (FTIH) Single and Repeat Dose Study - (11/09/11)

AASLD: Dose-Ranging Trial of PPI-461, a Potent New Pan-Genotypic HCV NS5A Inhibitor, in Patients with HCV Genotype-1 Infection - (11/07/11)

AASLD: Antiviral Activity/Resistance Monitoring of HCV Patients Treated for Three Days with the NS5A Inhibitor PPI-461 Reveals Rapid Emergence of Resistant HCV Variants - (11/07/11)

Inhibitex Nucelotide INX-189 Higher Dosing Increases Viral Load Reduction - Inhibitex reports third quarter financial results and recent corporate developments - (11/07/11)

AASLD: Antiviral Activity and Safety of INX-08189, a Nucleotide Polymerase Inhibitor, Following 7-Days of Oral Therapy in Naïve Genotype-1 HCV Patients - (11/07/11)

AASLD: Safety and Efficacy of Peginterferon Lambda-1a (Lambda) Compared With Peginterferon Alfa-2a (Alfa-2a) in HCV-Infected Patients (G1/2/3) With Compensated Cirrhosis: EMERGE Phase 2B Efficacy and Safety Results Through Week 12 - (11/10/11)


AASLD: Safety and Antiviral Activity of MK-5172, a Next Generation HCV NS3/4a Protease Inhibitor with a Broad HCV Genotypic Activity Spectrum and Potent Activity Against Known Resistance Mutants, in Genotype 1 and 3 HCV-Infected Patients - (11/07/11)

AASLD: MK-5172, a Second Generation HCV NS3/4A Protease Inhibitor is Active Against Common Resistance Associated Variants (RAVs) and Exhibits Cross-Genotype Activity - (11/07/11)

AASLD: Pharmacokinetics and Pharmacokinetic/Pharmacodynamic Relationship for MK-5172, a Novel Hepatitis C Virus (HCV) NS3/4A Protease Inhibitor, in Genotype 1 and Genotype 3 HCV-Infected Patients - (11/16/11)

AASLD: Discovery of MK-4882, a Novel Inhibitor of HCV NS5a with an Attractive Pre-clinical Profile - (11/07/11)

AASLD: The Effects of Combining Two Gilead Direct Acting Antivirals GS-9256+GS-9190, Ribavirin, and Pegylated Interferon on the Detection of Drug Resistance Mutations Early in Treatment of HCV - (11/15/11)

AASLD: Evaluation of Pre-Existing Levels of Y448H HCV NS5B Polymerase Mutant Using Viral Kinetics Monitored by Allele-Specific PCR in HCV Patients and Replicon Cells Treated with the HCV Non-Nucleoside Inhibitor Tegobuvir - (11/15/11)

AASLD: Characterization of HCV Resistance from a Multiple Dose Clinical Trial of GS-5885, a Novel HCV NS5A Inhibitor - (11/15/11)

AASLD: In Vitro Selection of Resistance to GS-9451, a Novel and Potent Inhibitor of HCV NS3 Protease - (11/15/11)



AASLD: Novel Hepatitis C Virus NS5A Inhibitors with Improved Potency Against Genotype-1a Replicons and Replicons Carrying Mutations Associated With Viral Resistance to 1st Generation NS5A Inhibitors - (11/10/11)

AASLD: Once-Daily Narlaprevir (NVR; SCH 900518) and Ritonavir (RTV) in Combination With Peginterferon Alfa-2b/Ribavirin (PR) for 12 Weeks Plus 12 Weeks PR in Treatment-Naive Patients With HCV Genotype 1 (G1): SVR Results From NEXT-1, a Phase 2 Study - (11/16/11)

AASLD: Safety and Efficacy of Vaniprevir (MK-7009) in Combination with Peg-interferon a-2a (Peg-IFN)/Ribavirin (RBV) in Genotype 1 Treatment-Experienced HCV-Infected Japanese Patients - (11/16/11)

AASLD: A Phase 2b Study of MK-7009 (vaniprevir) in Patients with Genotype 1 HCV Infection Who HaveFailed Previous Pegylated Interferon and Ribavirin Treatment - (11/15/11)


AASLD: Baseline and early on-treatment characteristics in HBeAg-positive patients with chronic hepatitis B infection achieving an early on-treatment response to pegylated interferon alfa-2a (40KD): interim results from the RGT study - (11/20/11)

AASLD: Patients with HBeAg-positive chronic hepatitis B with a maintained virologic response to entecavirachieved HBsAg clearance when switched to peginterferon alfa-2a (40KD) therapy (the OSST study) - (11/16/11)

AASLD: A novel combination regimen of peginterferon alfa-2a (40KD) and entecavir results in sustained post-treatment HBsAg clearance in HBeAg-positive chronic hepatitis B - (11/16/11)

AASLD: Peginterferon alfa-2a monotherapy as a strategy for achieving sustained response in patientsswitched from long-term nucleos(t)ide analog therapy: the results of 1 year follow up - (11/16/11)

AASLD: A response-guided approach to pegylated interferon alpha-2a (40KD) therapyto improve response rates in HBeAg-negative, genotype D patients - (11/16/11)

AASLD: Response rates are similar for patients with and without advanced fibrosis/cirrhosis, and highest with peginterferon alfa-2a (40KD) 180 μg for 48 weeks in the NEPTUNE study - (11/16/11)

AASLD: Five years of Treatment with Tenofovir DF for Chronic Hepatitis B Infection is Associated with Sustained Viral Suppression and Significant Regression of Histological Fibrosis and Cirrhosis - (11/14/11)

AASLD: No Detectable Resistance to Tenofovir Disoproxil Fumarate (TDF) Following up to 240 Weeks of Treatment in Patients with HBeAg+ and HBeAg-Chronic Hepatitis B Virus Infection - (11/14/11)

AASLD: Five years of Treatment with Tenofovir DF for Chronic Hepatitis B Infection in Asian Patients is Associated with Sustained Viral Suppression and Significant Regression of Histological Fibrosis and Cirrhosis - (11/14/11)

AASLD: Gilead Announces Positive Five-Year Data Showing Effect of Viread(R) on Liver Fibrosis and Cirrhosis Caused by Chronic Hepatitis B: '88% of patients on tenofovir in studies experienced reversal of fibrosis/cirrhosis' - press release - (11/14/11)

AASLD: Entecavir (ETV) monotherapy for 96 weeks is comparable to combination therapy with ETV plus tenofovir (TDF) in nucleos(t)ide-naïve patients with chronic hepatitis B (CHB): the BE-LOW study - (11/10/11)

AASLD: Phase IIIb Comparison of BARACLUDE® (entecavir) Monotherapy Versus BARACLUDE Plus Tenofovir Combination Shows No Statistical Difference Between Study Arms - press release - (11/10/11)

November 22, 2011

New MR imaging criteria with a diffusion-weighted sequence for the diagnosis of hepatocellular carcinoma in chronic liver diseases

J Hepatol. 2011 Jul;55(1):126-32. Epub 2010 Nov 23.
Assistance-Publique Hôpitaux de Paris, Hôpital Beaujon, Department of Radiology, Clichy, France.


To propose MRI criteria with a diffusion-weighted imaging (DWI) sequence for the diagnosis of hepatocellular carcinoma (HCC).

Patients, who underwent liver MRI with contrast-enhanced sequences and DWI between 2004 and 2008 and who had at least one confirmed HCC of at least 10mm, were included. Index diagnostic criteria were: (1) enhancement in the arterial-dominant phase and washout in the portal venous and/or equilibrium phases; (2) enhancement in the arterial-dominant phase and hyperintensity on DWI; (3) enhancement in the arterial-dominant phase and washout in the portal venous and/or equilibrium phases or hyperintensity on DWI. Two radiologists independently reviewed the corresponding sets of sequences (DWI alone; T1-weighted sequence before and after dynamic injection of gadolinium chelates; combined DWI-T1-weighted sequence). Inter-observer agreement and sensitivity were determined per nodule.

Ninety-one patients were included (109 HCCs). The sensitivity of conventional MRI criteria for the diagnosis of HCC was 59.6% for both radiologists. The sensitivity of enhancement in the arterial-dominant phase and hyperintensity on DWI was 77.1% or 76.1%, depending on the radiologist. The sensitivity of enhancement in the arterial-dominant phase and washout in the portal venous and/or equilibrium phases or hyperintensity on DWI was 84.4% or 85.3%, depending on the radiologist. The inter-observer agreement for the latter was very good (kappa coefficient 0.82). These results were consistent in HCCs smaller than 20mm.

The proposed criteria, based on the characteristics of lesions after gadolinium chelate administration and hyperintensity on DWI, significantly increased the sensitivity for the diagnosis of HCC compared to conventional criteria, regardless of tumor size.

Copyright © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.


Prediction of esophageal varices in hepatic cirrhosis by noninvasive markers.

Eur J Gastroenterol Hepatol. 2011 Sep;23(9):754-8.
Department of Medicine, Division of Gastroenterology and Gastrointestinal Endoscopy, Federal University of São Paulo, São Paulo, Brazil.


To determine whether Model for End-stage Liver Disease (MELD) Child-Turcotte-Pugh (CTP) classification, AST to platelet ratio index (APRI), and laboratory tests could predict the presence of esophageal varices (EV) or varices which need prophylactic therapy (medium or large size EV).

Three hundred patients with cirrhosis (193 men; mean age 53.1 years; majority with chronic C hepatitis) were prospectively analyzed. The presence of EV (any size and medium or large EV) was correlated with patients' characteristics (MELD, CTP classification, APRI, platelets count, and liver tests).

One hundred and seventy-one patients (57%) had EV, of whom 35% (105) had varices which need prophylactic therapy (VPT). The distribution of EV according to CTP classification was as follows: A, 49%; B, 75.3% and C, 80%. Independent predictors of EV were: MELD higher than 8 (P=0.02); APRI higher than 1.64 (P=0.01); platelet count lower than 93,000/mm³ (P<0.01); aspartate aminotransferase higher than 1.34 × UNL (P=0.01), and total bilirubin higher than 1 mg/dl (P=0.04). MELD higher than 8 had the highest discriminative value for presence of EV (sensitivity=80.1%; specificity=51.2%; area under receiver operating characteristics=0.68). Factors independently associated with VPT were: thrombocytopenia (<92,000/mm³; P<0.01) and aspartate aminotransferase higher than 1.47 × UNL (P=0.03). Platelet count lower than 92,000/mm³ had sensitivity of 65.7%, specificity of 57.9%, and an area under receiver operating characteristics of 0.62 for the presence of VPT.

High values on MELD are associated with EV and thrombocytopenia, with varices which need prophylactic therapy. As a result of their low sensitivity and specificity, it is suggested to maintain the recommendation of upper gastrointestinal endoscopy for all patients with cirhosis.


Impact of insulin resistance on sustained response in HCV patients treated with pegylated interferon and ribavirin: A meta-analysis

Journal of Hepatology
Volume 55, Issue 6 , Pages 1187-1194, December 2011

Pierre Deltenre, Alexandre Louvet, Maud Lemoine, Abbas Mourad, Laetitia Fartoux, Christophe Moreno, Jean Henrion, Philippe MathurinLawrence Serfaty

Received 28 December 2010; received in revised form 16 February 2011; accepted 3 March 2011. published online 13 April 2011.


Background & Aims
Recent studies suggested that SVR rates might be lower in HCV patients with insulin resistance (IR) than in patients without IR, but the extent of the impact of IR on treatment response has not been established. We aimed to confirm the role of IR assessed by the homoeostasis model assessment (HOMA-IR) on SVR and to determine its magnitude.

We performed meta-analysis of studies evaluating the impact of IR in HCV patients treated with pegylated interferon and ribavirin.

Fourteen studies involving 2732 patients were included. SVR was less frequent in patients with IR than in patients without IR (mean difference: −19.6%, 95% CI: −29.9% to −9.4%, p<0.001). In sensitivity analyses according to HCV-1 patients, patients with IR also less frequently attained a SVR than patients without IR (mean difference: −13.0%, 95% CI: −22.6% to −3.4%, p=0.008). In addition, the baseline HOMA-IR index was lower in responders than in non-responders (mean difference: −0.92, 95% CI: −1.53 to −0.32, p<0.001). In sensitivity analyses restricted to HCV-1 patients, the baseline HOMA-IR index remained lower in responders than in non-responders (mean difference: −0.63, 95% CI: −1.13 to −0.14, p<0.001).

HCV patients with IR have a 20% lower SVR than patients without IR. The baseline HOMA-IR index is a major determinant of SVR.


Beneficial IL28B genotype associated with lower frequency of hepatic steatosis in patients with chronic hepatitis C

Journal of Hepatology
Volume 55, Issue 6 , Pages 1195-1200, December 2011

Hans L. Tillmann, Keyur Patel, Andrew J. Muir, Cynthia D. Guy, Josephine H. Li, Xiang Qian Lao, Alexander Thompson, Paul J. Clark, Stephen D. GardnerJohn G. McHutchison, Jeanette J. McCarthy

Received 3 December 2010; received in revised form 1 March 2011; accepted 16 March 2011. published online 15 April 2011


Background & Aims
IL28B polymorphisms have been associated with both treatment induced and spontaneous clearance of hepatitis C virus (HCV). We previously found that LDL cholesterol levels were higher in chronic hepatitis C (CHC) patients with the CC genotype at the rs12979860 polymorphism, located proximal to the IL28 gene. Here we analyzed the association of steatosis with IL28B genotype in treatment naïve patients with CHC.

Two independent cohorts of 145 genotype 1 infected patients from an antifibrotic study and 180 genotype 1 patients from Duke were analyzed for the presence and severity of steatosis in relation to the rs12979860 polymorphism at the IL28B locus. TaqMan assay based genotyping classified three groups CC, CT, and TT.

CC genotype was associated with a lower prevalence of steatosis. In the antifibrotic study, steatosis was found in 47.6% (50/105) of IL28B non-CC vs. 22.5% (9/40; p=0.008) in CC patients. Similarly, steatosis was found in 67.4% (89/132) of non-CC patients compared to only 39.6% (19/48; p=0.001) of CC patients in the Duke cohort.

IL28B CC genotype is associated with less pronounced disturbances of lipid metabolism, as reflected both in serum lipoprotein levels and hepatic steatosis, in HCV infection.

VICTRELIS™ Now Available for Eligible Patients in Ontario

Canada NewsWire

Ontario first province to reimburse new chronic hepatitis C treatment

MONTREAL, Nov. 22, 2011 /CNW/ - Ontarians living with chronic hepatitis C now have publicly funded access to a new treatment option, as Ontario becomes the first province to reimburse VICTRELIS (boceprevir). The treatment qualified for a pre-approval rapid review under the Ontario Drug Benefit Act (ODBA), as it successfully met a pre-determined set of criteria, including offering substantial improvements of significant outcomes for the treatment of a serious disease.1

Boceprevir is a first-in-class oral hepatitis C virus (HCV) protease inhibitor for the treatment of chronic hepatitis C genotype 1 infection. It is to be used in combination with peginterferon alpha and ribavirin (peg/riba) in adult patients (18 years and older) with compensated liver disease, including cirrhosis, who are previously untreated or who have failed previous therapy.2 When added to peg/riba, boceprevir can significantly increase a patient's chance of clearing the virus from the body.3,4 The treatment was authorized for use in Canada in July of this year.

"The Canadian Liver Foundation is pleased that Ontario's public drug program has agreed to reimburse boceprevir for the treatment of chronic hepatitis C," says Dr. Morris Sherman, Chairman of the Canadian Liver Foundation. "Boceprevir represents a major advance in our ability to cure this disease, and as a result, fewer patients will have to struggle with the consequences of end-stage liver disease, liver transplants and liver cancer. We applaud the research efforts that led to this breakthrough and hope other provinces will follow Ontario's lead and rapidly reimburse this important treatment."

Eligibility criteria for boceprevir can be accessed through the following link:

Hepatitis C in Canada

An estimated 250,000 individuals in Canada are infected with HCV and there are 3,200 to 5,000 newly infected individuals each year.5 HCV damages the liver and may lead to serious complications, including death, when left untreated.6 It is the leading cause of liver transplants in Canada.7

About Merck

Today's Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our medicines, vaccines, biologic therapies, and consumer and animal products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information about our operations in Canada, visit

Forward-Looking Statement

This news release includes "forward-looking statements" within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. Such statements may include, but are not limited to, statements about the benefits of the merger between Merck and Schering-Plough, including future financial and operating results, the combined company's plans, objectives, expectations and intentions and other statements that are not historical facts. Such statements are based upon the current beliefs and expectations of Merck's management and are subject to significant risks and uncertainties. Actual results may differ from those set forth in the forward-looking statements.

The following factors, among others, could cause actual results to differ from those set forth in the forward-looking statements: the possibility that the expected synergies from the merger of Merck and Schering-Plough will not be realized, or will not be realized within the expected time period; the impact of pharmaceutical industry regulation and health care legislation; the risk that the businesses will not be integrated successfully; disruption from the merger making it more difficult to maintain business and operational relationships.

Merck's ability to accurately predict future market conditions; dependence on the effectiveness of Merck's patents and other protections for innovative products; the risk of new and changing regulation and health policies in the United States and internationally and the exposure to litigation and/or regulatory actions.

Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck's 2010 Annual Report on Form 10-K and the company's other filings with the Securities and Exchange Commission (SEC) available at the SEC's Internet site (

TM Trademark of Schering Corporation, a subsidiary of Merck & Co., Inc. Used under license.

1 Guidelines for Rapid Review Submissions.
Accessed November 15, 2011, p. 1.
2 VICTRELIS, Product Monograph, July 27, 2011, p. 3.
3 Poordad, F., et al., for the SPRINT-2 Investigators.
 Boceprevir for Untreated Chronic HCV Genotype 1 Infection.
N Engl J Med 2011; 364:1195-1206, page 1195.
4 Bacon, B.R., et al., for the HCV RESPOND-2 Investigators.
Boceprevir for Previously Treated Chronic HCV Genotype 1
Infection. N Engl J Med 2011; 364:1207-1217, p. 1207.
5 Canadian Institutes of Health Research.
About the Hep C Research Initiative.
Accessed November 2, 2011.
6 Public Health Agency of Canada.
Accessed November 2, 2011.
7 Canadian Liver Foundation.
Accessed November 2, 2011.


University launches iphone app for hepatitis treatment

Public release date: 22-Nov-2011

Contact: Sarah Stamper
University of Liverpool

The University of Liverpool has launched an iphone app, HEP i-chart, that provides Hepatitis C (HCV) patients with quick and easy access to the latest information about drug interactions.

Hepatitis C was first discovered in the 1980s when it became apparent that there was a new virus (not the already known hepatitis A or B) causing liver damage. Hepatitis C causes inflammation and swelling of the liver. It is estimated that over 170million individuals – representing 3% of the world's population – are chronically infected with the Hepatitis C virus (HCV). Statistically, as many people are infected with HCV as are with HIV.

Since its identification, drug treatment to eradicate the virus has advanced greatly, especially in the last few years. Two new drugs have recently been licensed for treatment of HCV, and there are more drugs in development.

HEP i-chart is based on the website ( developed at the University by Professor David Back and Professor Saye Khoo which provides a comprehensive online guide to the interactions between anti-hepatitis drugs and other drugs. It is a tool that provides

Hepatitis C patients and healthcare professionals with immediate access to up-to-date information on potential drug interactions between HCV drugs, and other drugs that the patient may be prescribed as well as over-the-counter, recreational or herbal medications.

Existing HCV drugs, newly licensed drugs and drugs in development can have interactions with each other and with other drugs which can impact on their effectiveness – sometimes with serious consequences. For this reason, some drug combinations must not be used, whilst others must be given with caution, possibly requiring adjustment or monitoring.

Professor of Pharmacology, David Back, said: "We are delighted to launch with our partners – KnowledgePoint360, MSD and Janssen- this new i-phone application that provides Hepatitis C patients and healthcare professionals with instant and easy access to information about HCV drug interactions which is relevant and reliable and up-to-date. This resource is especially important as new HCV drug treatments are approved and come into use."

Professor Graham Foster, President of the British Association for the Study of the Liver (BASL) said: "This new app, HEP i-chart, is a timely and much-needed resource for HCV patients as the number of new drugs which are available to treat Hepatitis C increases."


Organ Transplants and Cancer Risk

November 21, 2011

Organ transplant recipients have a high risk of developing 32 different types of cancer, according to a new study. Future research to understand why may lead to better strategies for preventing cancer among transplant recipients.

In 2010, over 28,000 organ transplantations were performed in the U.S., including 16,899 kidney, 6,291 liver, 2,333 heart and 1,770 lung transplants. Transplant recipients are known to be at a higher risk for developing cancer than the general population. But past studies of cancer risk in transplant recipients focused mainly on those who received kidney transplants. Other studies were too small to accurately estimate risk for all but the most common cancer types.

For a more comprehensive look, a research team led by Dr. Eric A. Engels of NIH's National Cancer Institute (NCI) evaluated medical data from more than 175,000 transplant recipients—about 40% of all organ transplant recipients in the country. Their report appeared in the November 2, 2011, issue of the Journal of the American Medical Association.

The researchers found a twofold overall increased risk of cancer among transplant recipients. They noted elevated risk for 32 different types of cancer, some known to be related to infectious agents (such as anal cancer and Kaposi sarcoma) and others unrelated to infections (such as melanoma and thyroid cancer). The most common cancers among transplant recipients were non-Hodgkin lymphoma (14% of all cancers in transplant recipients), lung cancer (13%), liver cancer (9%) and kidney cancer (7%).

The risk of cancer was affected by the type of transplant. Lung cancer risk, for example, was highest in lung recipients. Smoking-related disease is often the reason for a lung transplant, and lung cancer typically arises in the remaining diseased lung rather than the transplanted one. The risk of liver cancer was elevated only among liver recipients. That might be partly explained by hepatitis B or C infection in the transplanted liver or by the fact that diabetes is common among transplant recipients. The risk of kidney cancer, in contrast, increased for all recipients.

“While transplantation is a life-saving therapy for patients with end-stage organ disease, it also puts recipients at an increased risk for developing cancer, in part because of medications administered to suppress the immune system and prevent rejection of the organ,” Engels says. “The cancer risk among transplant recipients resembles that of people with HIV infection, whose risk is elevated for infection-related cancers due to immunosuppression.”

The researchers now plan to focus on the cancers that occur at higher rates among transplant recipients. They aim to discover how medical conditions and immunosuppressive medications contribute to cancer risk. “In addition, we hope our findings will stimulate other research into the carcinogenic mechanisms associated with organ transplantation,” Engels says.


Liver Cancer Treatment Turns Up the Heat on Chemotherapy

By John Fauber, Reporter, Milwaukee Journal Sentinel/MedPage Today

Published: November 21, 2011

As Mark Vetter lay on the operating table, doctors isolated his liver and began bathing it in a heated, highly toxic poison sent through the organ's blood vessels.

Over the course of an hour, cancer cells in the liver started to die and continued doing so for days.

The operating room at Froedtert Hospital in the Milwaukee area was filled with onlookers who wanted to get a glimpse because the treatment was one that few doctors have witnessed.

"If everything is successful it will kill the remaining cancer cells and it is a healthy liver," a hopeful Vetter said a couple weeks after recovering from the surgery.

For someone like Vetter, who hopes to live for years, there is enough science to offer a glimmer of hope, but also the dark reality that the treatment may only offer another year or so.

The therapy he chose to undergo may have its physiological underpinnings in a theory that has come to be known as the "Lance Armstrong Effect."

The legendary cyclist bounced back from testicular cancer that had metastasized to his lungs and brain, and he went on to win several Tour de France races.

The Armstrong Effect

Why did Armstrong and nearly 70% of other testicular cancer patients survive, even when the disease had metastasized to other parts of the body?

The answer, according to proponents of this theory, lies in anatomy -- the testicles normally are a few degrees cooler than the rest of the body, and when testicular cancer cells spread to other, warmer environments inside the body, they are confronted by a heat wave.

In that stressed state, the theory goes, the cancer cells become more susceptible to treatments such as chemotherapy and radiation.

The combination of heat and chemo may be a promising approach to treating intractable cancers, said Robert Getzenberg, MD, the Johns Hopkins University School of Medicine researcher who coined the term "Lance Armstrong Effect" five years ago in a commentary in the Journal of the American Medical Association.

"We have not had much success with cancer," Getzenberg said. "There are few things that really work. Every drug we come up with, cancer develops a resistance to," Getzenberg said.

Old Idea Finds New Believers

For decades, doctors have known that heat can kill cancer cells. Dating back to the 1960s, small trials of combining heat and chemotherapy were conducted, but the treatment never caught on mainly because of its complexity and a lack of data showing a clear survival benefit, said H. Richard Alexander, MD, associate chairman of clinical research at the University of Maryland Medical Center.

But in the 1990s, Alexander and other researchers began finding benefit in difficult-to-treat cancers that had spread to the liver.

"If (liver perfusion) were just a pill, the FDA would approve it immediately because it is as good as anything else we have tried," he said. "In some patients you see very dramatic results. In some cases, you can make tumors disappear from x-rays."

But tumors can come back. So far, the gold standard of research -- a large, randomized clinical trial -- has yet to be done. So data on the survival benefit remain lacking.

To date, most of the observational research suggests that average survival is extended about a year.

At the University of Pittsburgh Medical Center, about 25 liver perfusion cases are done a year, said cancer surgeon David Bartlett, MD.

Average survival is about two years, he said. About 5% of patients live five years. One man still is alive 12 years after undergoing the treatment, Bartlett said.

Not Too Hot, Not Too Cold

At Froedtert, the doctors use a basic, highly invasive approach:
  • Wheel the patient to the operating room
  • Make a long incision in the abdomen
  • Isolate the liver with clips, catheters, and cannulas, and perfuse it with the drug melphalan
  • The drug is heated to about 102 degrees and mixed at concentration 20 times stronger than a standard chemotherapy dose
Others are in the early stages of testing more sophisticated methods for using heat and chemo, including the use of iron oxide and gold nanoparticles that have been chemically bonded with antibodies designed that seek out specific cancer cells. With the tiny metallic particles inside, the tumors, but not healthy tissue, then are heated using friction caused by radiofrequency or alternating magnetic field devices.

"We can heat them so much that we can burn them up," Getzenberg said.

The ideal approach, though, which now is being tested with prostate cancer in lab and animal models, involves heating the tumors to 107 degrees, which makes them much more vulnerable to chemotherapy agents, he said. Such nanoparticle and heat cancer therapies remain unproven and likely are a few years down the road

The "If" Factor

From his perspective as a patient undergoing a newly discovered "old" therapeutic approach, the treatment is just one more "if" for Vetter.

If he had not gone in for a routine eye exam two years ago, doctors would not have found the tumor in his left eye and he might be dead -- he's one of about five in one million people a year who develop ocular melanoma, a disease that often metastasizes to the liver.

If he had preferred, he could have traveled hundreds of miles to one of a couple centers in the country that specialize in the unconventional treatment. Instead, he chose to be one of the first such patients to undergo that unconventional treatment at a center in his hometown.

Of course, there is the biggest if: if this treatment works, how long will he live?

At 66, Vetter, a Milwaukee area private labor attorney, is no Lance Armstrong.

He looks trim and fit, hardly like someone who had been battling an often fatal disease for more than two years.

The Process

The treatment Vetter underwent lasted about an hour, "the most tolerable duration," according to T. Clark Gamblin, MD, one of the Froedtert/Medical College of Wisconsin cancer surgeon who operated on Vetter.

The trick is to get the right mix of chemo, heat, and time so to be lethal to cancer cells without causing too much harm to healthy liver cells. While some normal liver cells may die, that's acceptable because the liver has the ability to regenerate tissue.

"You are putting the liver on bypass," said Kiran Turaga, MD, a Froedtert/Medical College cancer surgeon. "It's like the liver is out of the body."

Vetter's surgery was the second such case at the hospital and the latest in a long line of treatments he has tried.

As a veteran of the cancer war, he knows he will be undergoing continual monitoring in the months to come.

He also says he understands there is no way to know how much the treatment will help.

"I have not changed much of anything about the way I live my life," he said in a recent interview from his Milwaukee area home. "My goal is to be sitting in this room in 20 years."


New treatments of chronic hepatitis C

Presse Med. 2011 Nov 4. [Epub ahead of print]

Hôpital Cochin et Inserm U1016, Assistance publique-Hôpitaux de Paris, université Paris-Descartes, unité d'hépatologie, 75014 Paris, France.

The current treatment of chronic hepatitis C since several years, the association of pegylated interferon and ribavirine, allows to obtain a virological eradication in 55% of patients, all genotypes and 45% of those infected with the genotype 1, the most prevalent. The cure, defined by an undetectable viremia 24 weeks after the discontinuation of treatment is associated to a improvement of the prognosis of the patients with a decrease of mortality and morbidity. The development of news antiviral C molecules, efficient against the genotype 1, two protease inhibitors, boceprevir or telaprevir (which approval has been recently obtained), in association with pegylated interferon and ribavirine, allows to obtain a viral eradication in 70 to 75% of cases, with a reduction of treatment duration to 24 weeks in half of patients. This evolution will modify the therapeutic indications, the therapeutic schemas, the virologic follow-up, the risk factors of sustained virological reponse, the tolerance with the appearance of new adverse effects.

Copyright © 2011. Published by Elsevier Masson SAS.

November 20, 2011

No HIV Disease Progression in Transplant Recipients

Sandra Yin

November 18, 2011 (Bethesda, Maryland) — Now that people infected with HIV are living longer, physicians are seeing a growing number who need kidney or liver transplants because of comorbid conditions. But what happens when you take patients in an immunosuppressed population, give them new organs, and further immunosuppress them with drugs to prevent rejection of those organs?

HIV does not progress in HIV-positive transplant recipients, according to findings from a study titled "Opportunistic Infections and Neoplasms Following Liver and Kidney Transplantation in the HIV Infected Recipient," which was presented at the 13th International Conference on Malignancies in AIDS and Other Acquired Immunodeficiencies (ICMAOI) here at the National Institutes of Health (NIH).

But there is a much higher incidence of organ rejection, indicating a dysregulated immune system rather than an absence of immunity, investigators said.

"The take-home message is that HIV is not the issue," Peter Stock, MD, PhD, professor of surgery at the University of California at San Francisco. He was the principal investigator of a multicenter trial in patients with HIV who received liver or kidney transplants.

"It's the comorbidities that are the issue. In other words, we did not see progression of HIV in any of the transplantations. Nor did we see an increase in the incidence of AIDS-related malignancies."

The aim of the trial was to evaluate the effect of HIV infection on graft function and survival, study the effect of transplantation and post-transplant immunosuppression on HIV progression and markers of immune function and activity, and describe the pharmacokinetic interactions between immunosuppressive agents and antiretroviral agents.

The NIH-funded trial involved 150 kidney and 125 liver transplants at 18 centers across the United States, with 3- to 4-year follow up. Patients selected for the study had CD4+ T-cell counts greater than 200 cells/mm3 for kidney recipients and greater than 100 cells/mm3 for liver recipients. For kidney patients, the HIV viral load had to be undetectable while the patients were receiving a stable antiviral regimen. A detectable HIV viral load was permitted in liver recipients as long as the HIV providers said that the virus could be suppressed after transplantation. Researchers excluded patients with opportunistic infections that could not be treated, such as cryptosporidiosis and visceral Kaposi's sarcoma. Post-treatment management included prophylaxis against opportunistic infections, immunosuppression, management of rejection, and antiretroviral therapy.

Of 150 kidney transplant recipients, 20% were co-infected with hepatitis C virus (HCV) at baseline. The median follow-up was 3.6 years. One in 4 patients had a history of opportunistic infections before transplantation.

For the 150 kidney transplant recipients, researchers reported that HIV generally remained suppressed and CD4 counts remained relatively stable. When they used antithymocyte globulin, patients' CD4 counts were wiped out for a year and they still saw minimal opportunistic infections in the year it took for the CD4 counts to come back. The investigators did see a higher incidence of serious bacterial infections, about 2-fold greater, in the patients whose CD4+ counts were deleted. Both patient and graft survival were similar to that in the general population at 1 and 3 years.

The main problem, Dr. Stock said, was a high incidence of organ rejection, 2- to 3-fold higher than what they saw in HIV-negative patients. Research is underway to explore the mechanism behind the high rate of rejection. "But it is real," he said. "It clarifies to me that this is not the absence of an immune system, it is the presence of a very dysregulated immune system."

Among 125 liver transplant recipients, 69% at baseline were co-infected with HCV, 36% had hepatocellular carcinoma, and 12% had a history of opportunistic infections before transplantation. Median duration of follow-up was 4 years.

Compared with patients mono-infected with hepatitis B virus (HBV), HIV-positive liver transplant recipients co-infected with HBV did just as well with their transplants 5 years out. "I think this is the proof that HIV is not the problem," said Dr. Stock. "It's the co-pathogens that are the problem after transplantation. We do a pretty good job of controlling HIV."

HCV was a different story, he said. The 3-year survival rate for the HCV-HIV co-infected group was 64%, compared with 75% for the group with HCV infection only.

Not surprisingly, many centers are balking at transplantations for co-infected patients with HCV, but not those with HBV, because the low survival rate is affecting center-specific results, Dr. Stock said. Those rates could endanger Medicare funding and scare third-party payer referrals away.

Graft survival in co-infected patients at 3 years was 59%, compared with 67% in the mono-infected controls.

The incidence of rejection in the HIV-HCV co-infected patients was 2-fold higher, and 50% of those rejection episodes happened early on.

Treating those rejections is problematic because rejection becomes an independent predictor of graft loss and severe HCV recurrence, Dr. Stock said. Control over the virus and the co-pathogen is lost when these patients are immunosuppressed. "That begs the question of what we're doing to all the viruses that may be associated with cancer," he observed.

"I think the striking thing about the cancer risk in those patients, which is what Dr. Stock was presenting, is that it's not a lot higher than what he observed," Eric Engels, MD, MPH, senior investigator at the National Cancer Institute's Division of Cancer Epidemiology and Genetics, told Medscape Medical News.

There certainly are some cancers, but no more than you would probably expect in a transplant population that did not have HIV infection, Dr. Engels said.

13th International Conference on Malignancies in AIDS and Other Acquired Immunodeficiencies (ICMAOI); Abstract #P6. Presented November 8, 2011.